Naphthalene derivatives

ABSTRACT

The present invention relates to a naphthalene derivative. More particularly, it relates to a naphthalene derivative exhibiting an excellent activity as a drug.

This is a division of U.S. application Ser. No. 07/790,541, filed Nov.12, 1991.

BACKGROUND OF THE INVENTION AND PRIOR ARTS

Although various nonsteroidal anti-inflammatory drugs have already beenput on the market, they are all unsatisfactory in respect of efficacy,so that the development of an anti-inflammatory drug from newstandpoints has been eagerly expected.

It has already been known that the inhibition of production ofprostaglandins (PGs) brings about an anti-inflammatory effect.Meanwhile, many studies have recently been made on leukotrienes (LTs) tomake their physiological activities apparent. That is, LTB₄ exhibits anactivity of highly activating the migration of leukocyte to cause theexcess accumulation thereof, thus contributing to the acceleration ofinflammatory reactions, while LTC₄ and D₄ have been ascertained toexhibit an effect of enhancing the permeability of a blood vessel.Accordingly, it is conceivable that a more excellent anti-inflammatorydrug can be developed if the inhibitory activity against LTs productionis combined with that against PGs production at a well-balanced activityratio. Further, such an anti-inflammatory drug may be effectivelyapplied to asthma, inflammatory dermatitis, inflammatory entericdiseases, arthritis and so on by virtue of its pathological effects.

No drug has been developed as yet from the standpoint described above.

Under these circumstances, the inventors of the present invention haveeagerly studied for many years and have found that a naphthalenederivative which will be described below acts as an excellentanti-inflammatory drug. The present invention has been accomplished onthe basis of this finding.

With respect to naphthalene derivatives, for example, Japanese PatentLaid-Open No. 263943/1986 discloses naphthalene derivatives exhibitingan inhibitory activity against 5-lipoxygenase, while Aust. J. Chem., 30,2241 (1977) discloses those substituted with an alkenylcarboxylic acidgroup at the 1-position. However, not only these derivatives aredistinguishable from those of the present invention in respect ofchemical structure, but also these documents are silent on the efficacythereof as a drug.

SUMMARY OF THE INVENTION

The compound of the present invention is a naphthalene derivativerepresented by the following general formula (I) or a pharmacologicallyacceptable salt thereof: ##STR1## wherein R¹ stands for a hydrogen atomor a lower alkyl, acyl or arylalkyl group;

R² stands for a hydrogen atom or a lower alkyl, lower alkoxy,cycloalkoxy or acyl group;

R³ stands for a hydroxyl group, a group capable of forming an estertogether the carboxyl group represented by the formula: ##STR2## whereinR³ is a hydroxyl group, or a group represented by the formula: ##STR3##(wherein R¹⁰ and R¹¹ may be the same or different from each other andeach stands for a hydrogen atom, a hydroxyl, lower alkyl, lower alkoxy,aryl, heteroaryl group or a group represented by the formula:--(CH₂)_(q) --COOH (wherein q is an integer of 1 to 2), or alternativelyR¹⁰ and R¹¹ may form a ring which may contain a nitrogen, oxygen orsulfur atom together with the nitrogen atom to which R¹⁰ and R¹¹ arebonded);

Z stands for a group represented by the formula: ##STR4## (wherein R⁵and R⁶ may be the same or different from each other and each stands fora hydrogen atom or a lower alkyl, alkenylalkyl, alkynylalkyl or arylgroup, an arylalkyl group, the aryl group of which may be substituted, ahalogen atom or a heteroarylalkyl, cycloalkyl, cycloalkylalkyl, loweralkoxyalkyl, heterocycloalkyl or cyano group, or alternatively R⁵ and R⁶may form a ring together with the carbon atom to which R⁵ and R⁶ arebonded), a group represented by the formula: ═N-OR⁷ (wherein R⁷ standsfor a lower alkyl group) or an oxygen atom;

Y stands for a group represented by the formula: --(CH₂)n-- (wherein nis 0 or integer of 1 to 2) or a group represented by the formula:##STR5## (wherein R⁸ and R⁹ may be the same or different from each otherand each stands for a lower alkyl group); and

R⁴ stands for a hydrogen atom, a lower alkyl group or a grouprepresented by the formula: ##STR6## (wherein p is 0 or an integer of 1to 3 and R¹² stands for a hydrogen or halogen atom or a lower alkyl orlower alkoxy group).

Among these naphtahlene derivatives as defined the general formula (I)or pharmacologically acceptable salts thereof, a compound that R⁴ in thegeneral formula (I) is a benzyl group is preferable.

Among these naphtahlene derivatives as defined the general formula (I)or pharmacologically acceptable salts thereof, a compound that R¹ in thegeneral formula (I) is a hydrogen atom or a lower alkyl group ispreferable, and a compound that R¹ in the general formula (I) is amethyl group is more preferable.

Among these naphtahlene derivatives as defined the general formula (I)or pharmacologically acceptable salts thereof, a compound that R² in thegeneral formula (I) is a lower alkoxyl group is preferable, and acompound that R² in the general formula (I) is a methoxyl group is morepreferable.

Among these naphtahlene derivatives as defined the general formula (I)or pharmacologically acceptable salts thereof, a compound that R³ in thegeneral formula (I) is a hydroxyl group is preferable.

Among these naphtahlene derivatives as defined the general formula (I)or pharmacologically acceptable salts thereof, a compound that Y in thegeneral formula (I) is a group represented by the formula: --(CH₂)_(n)-- (wherein n is 0) is preferable.

Among these naphtahlene derivatives as defined the general formula (I)or pharmacologically acceptable salts thereof, a compound that Z in thegeneral formula (I) is a group represented by the formula: ##STR7##(wherein R⁵ and R⁶ may be the same or different from each other and eachstands for a hydrogen atom, a lower alkyl group, an alkenylalkyl group,an arylalkyl group whose aryl group may be substituted or a halogenatom) is preferable.

Among these naphtahlene derivatives as defined the general formula (I)or pharmacologically acceptable salts thereof, a compound that in thegeneral formula (I), R¹ is a hydrogen atom, R² is a methoxy group, R³ isa hydroxyl group, Y is a group represented by the formula: --(CH₂)_(n)-- (wherein n is 0), Z is a group represented by the formula: ##STR8##(wherein R⁵ and R⁶ may be the same or different from each other and eachstands for a hydrogen atom, a lower alkyl group, an alkenylalkyl group,an arylalkyl group whose aryl group may be substituted or a halogenatom), and R⁴ is a benzyl group is preferable.

Among these naphtahlene derivatives as defined the general formula (I)or pharmacologically acceptable salts thereof, a compound selected fromthe group consisting of the below listed naphtahlene derivatives ispreferable.

(Z)-2-(5-benzyl-4-hydroxy-3-methoxy-1-naphtyl)-2-butenoic acid;

(Z)-2-(5-benzyl-4-hydroxy-3-methoxy-1-naphtyl)-2-pentenoic acid;

(Z)-2-(5-benzyl-4-hydroxy-3-methoxy-1-naphtyl)-2-hexenoic acid;

(Z)-2-(5-benzyl-4-hydroxy-3-methoxy-1-naphtyl)-4-methoxy-2-pentenoicacid;

(Z)-2-(5-benzyl-4-hydroxy-3-methoxy-1-naphtyl)-2,5-hexadienoic acid;

(Z)-2-(5-benzyl-4-hydroxy-3-methoxy-1-naphtyl)-2-heptenoic acid;

(Z)-2-(5-benzyl-4-hydroxy-3-methoxy-1-naphtyl)-3-propenoic acid;

(Z)-2-(5-benzyl-4-hydroxy-3-methoxy-1-naphtyl)-4-phenyl-2-butenoic acid;

(Z)-2-(5-benzyl-4-hydroxy-3-methoxy-1-naphtyl)-3-cyclohexyl-2-propenoicacid;

(Z)-2-(5-benzyl-4-hydroxy-3-methoxy-1-naphtyl)-4,4-dimethyl-2-pentenoicacid;

2-(5-Benzyl-4-hydroxy-3-methoxy-1-naphtyl)-2-propenoic acid;

2-(5-Benzyl-4-hydroxy-3-methoxy-1-naphtyl)-2-butenoic acid;

(E)-2-(5-benzyl-4-hydroxy-3-methoxy-1-naphtyl)-2-butenoic acid;

2-(5-Benzyl-4-hydroxy-3-methoxy-1-naphtyl)-3,3-dichloro-2-propenoicacid;

(Z)-2-(5-benzyl-4-hydroxy-3-methyl-1-naphtyl)-2-butenoic acid;

2-(5-Benzyl-4-hydroxy-3-methyl-1-naphtyl)-3-methyl-2-butenoic acid;

(E)-2-(5-benzyl-4-hydroxy-3-methoxy-1-naphtyl)-2-pentenoic acid;

(E)-2-(5-benzyl-4-hydroxy-3-methoxy-1-naphtyl)-2-hexenoic acid;

(Z)-2-(5-benzyl-4-hydroxy-3-ethoxy-1-naphtyl)-2-butenoic acid;

(Z)-2-(5-benzyl-4-acetoxy-3-methoxy-1-naphtyl)-4-methyl-2-pentenoicacid;

(Z)-2-(5-benzyl-4-acetoxy-3-methoxy-1-naphtyl)-2-hexenoic acid;

(E)-2-(5-benzyl-4-acetoxy-3-methoxy-1-naphtyl)-2-butenoic acid;

(Z)-2-(5-benzyl-4-acetoxy-3-methoxy-1-naphtyl)-2-butenoic acid;

(Z)-2-(5-benzyl-4-acetyloxy-3-methoxy-1-naphtyl)-2-pentenoic acid; and

(Z)-2-(5-benzyl-4-hydroxy-3-methoxy-1-naphtyl)-4-methyl-2-pentenoicacid.

A pharmaceutical composition of the present invention comprises atherapeutically effective amount of the above-mentioned naphthalenederivative or the pharmacologically acceptable salt thereof and apharmacologically acceptable carrier.

A method for treatment of a disease of the present invention comprisesadministering a pharmaceutically effective amount of the above-mentionednaphthalene derivative or the pharmacologically acceptable salt thereofto a patient suffering from a disease which the production ofprostaglandin is rised.

A method for treatment of a disease of the present invention comprisesadministering a pharmaceutically effective amount of the above-mentionednaphthalene derivative or the pharmacologically acceptable salt thereofto a patient suffering from a disease which the production ofleukotrienes is rised.

A method for treatment of a disease of the present invention comprisesadministering a pharmaceutically effective amount of the above-mentionednaphthalene derivative or the pharmacologically acceptable salt thereofto a patient suffering from an inflammatory disease.

A method for treatment of a disease of the present invention comprisesadministering a pharmaceutically effective amount of the above-mentionednaphthalene derivative or the pharmacologically acceptable salt thereofto a patient suffering from a disease selected from the group consistingof chronic rheumatoid arthritis, osteoarthritis, shoulder periarthritis,cervicobrachial syndrome and lumbago.

Furthermore, use of the present invention comprises the use of theabove-mentioned naphthalene derivative or the pharmacologicallyacceptable salt thereof for the making of a medicament for treating adisease which the production of prostaglandin is rised.

Use of the present invention comprises the use of the above-mentionednaphthalene derivative or the pharmacologically acceptable salt thereoffor the making of a medicament for treating a disease which theproduction of leukotrienes is rised.

Use of the present invention comprises the use of the above-mentionednaphthalene derivative or the pharmacologically acceptable salt thereoffor the making of a medicament for treating an inflammatory disease.

Use of the present invention comprises the use of the above-mentionednaphthalene derivative or the pharmacologically acceptable salt thereoffor the making of a medicament for treating a disease selected from thegroup consisting of chronic rheumatoid arthritis, osteoarthritis,shoulder periarthritis, cervicobrachial syndrome and lumbago.

The intermediate of the present invention is a naphthalene derivativerepresented by the following general formula (A): ##STR9## wherein R^(a)means a benzyl group, R^(b) stands for a hydrogen atom or a lower alkylgroup, R^(c) stands for a hydrogen atom or a lower alkyl group and R^(d)represents a hydrogen atom or a group represented by the formula:##STR10## (wherein R^(e) stands for a hydroxyl group or a lower alkylgroup).

Among these intemediates (naphthalene derivatives) as defined thegeneral formula (A), a compound selected from the group consisting ofthe below listed naphtahlene derivatives is preferable. ##STR11##

DETAILED DESCRIPTION OF THE INVENTION

In this specification, the position numbers of carbon atoms constitutingthe naphthalene ring are as follows: ##STR12##

In the above definition of the compound (I) according to the presentinvention, the lower alkyl group defined with respect to R¹, R², R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² is a straight-chain or branched alkylgroup having 1 to 6 carbon atoms and examples thereof include methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl(amyl), isopentyl, neopentyl, tert-pentyl, 1-methylbutyl,2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl,2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl,3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl,1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropylgroups. Among these groups, methyl group, ethyl group, propyl group andisopropyl group are desirable.

The lower alkoxy group defined with respect to R², R¹⁰, R¹¹ and R¹² isone derived from the above-mentioned lower alkyl group having 1 to 6carbon atoms and preferable examples thereof include methoxy group,ethoxy group, n-propoxy group, isopropoxy group and n-butoxy group,among which methoxy group is most desirable.

The halogen atom defined with respect to R⁵, R⁶ and R¹² is chlorine,bromine, iodine or fluorine.

The cycloalkyl group defined with respect to R⁵ and R⁶ is one having 3to 7 carbon atoms and examples thereof include cyclopropyl group,cyclobutyl group, cyclopentyl group, cyclohexyl group and cycloheptylgroup.

The cycloalkylalkyl group defined with respect to R⁵ and R⁶ is onederived from the above-mentioned cycloalkyl group and representativeexamples thereof include cyclopentylmethyl group, cyclopropylmethylgroup, cyclohexylmethyl group and cyclohexylethyl group.

The aryl group defined with respect to R², R⁵, R⁶, R¹⁰ and R¹¹ includesa phenyl group, a naphthyl group and so on which may be substituted witha lower alkyl group such as a methyl group, a ethyl group, a halogenatom and a lower alkoxy group.

The arylalkyl group defined with respect to R¹, R⁵ and R⁶ is one derivedfrom the above-mentioned aryl group. The most desirable examples thereofinclude benzyl group and phenethyl group, the aryl group of which may besubstituted with a methyl group, a ethyl group or a halogen atom.

The heteroaryl group defined with respect to R¹⁰ and R¹¹ is aheterocyclic group such as a pyridyl group, a furyl group and apyrimidyl group.

The lower alkoxyalkyl group defined with respect to R⁵ and R⁶ is onederived from the above-mentioned lower alkoxy group and examples thereofinclude methoxyethoxy group, methoxypropoxy group and ethoxyethoxygroup.

The acyl group defined with respect to R² is a residue of an organicacid such as an aliphatic saturated or unsaturated carboxylic acid and acarbocyclic or heterocyclic carboxylic acid and particular examplesthereof include lower alkanoyl groups such as formyl group, acetylgroup, propionyl group, butyryl group, isobutyryl group, valeryl group,isovaleryl group and pivaloyl group; aroyl groups such as benzoyl group,toluoyl group and naphthoyl group; and heteroaroyl groups such as furoylgroup, nicotinoyl group and isonicotinoyl group.

Further, R¹⁰ and R¹¹ may form a ring which may contain a nitrogen,oxygen or sulfur atom together with the nitrogen atom to which R¹⁰ andR¹¹ are bonded and examples of such a ring include ##STR13##

The cycloalkoxy group defined with respect to R² is one derived from theabove-mentioned cycloalkyl group and examples thereof include ##STR14##

The alkenylalkyl or alkynylalkyl group defined with respect to R⁵ and R⁶is one derived from the above-mentioned lower alkyl group having 1 to 6carbon atoms in which one or two double or triple bonds are contained,and representative examples thereof include 2-propenyl group and2-methylbutenyl group.

When R³ is a hydroxyl group, the group represented by the formula:##STR15## is a carboxyl group (--COOH). R³ may be a group capable offorming an ester together with the carboxyl group. Representativeexamples of the group include lower alkoxy groups such as methoxy groupand ethoxy group and cycloalkoxy groups.

R⁵ and R⁶ may form a ring and examples of such a ring are as follows:##STR16##

If necessary, these rings may be substituted with a lower alkyl groupsuch as a methyl group and a halogen atom.

Further, the heteroarylalkyl group defined with respect to R⁵ and R⁶ isone derived from the heteroaryl group defined above with respect to R¹⁰and R¹¹ and examples thereof include pyridylmethyl group, thienylmethylgroup and thienylethyl group.

The pharmacologically acceptable salt according to the present inventionmay be any conventional nontoxic one and examples thereof includeinorganic acid salts such as hydrochloride, hydrobromide, sulfate andphosphate; organic acid salts such as acetate, maleate, tartrate,methanesulfonate, benzenesulfonate and toluenesulfonate; and amino acidsalts such as argininate, aspartate and glutamate. Further, thederivative of the present invention may form a metal salt such as sodiumsalt, potassium salt, calcium salt and magnesium salt. Thepharmacologically acceptable salt of the present invention includesthese metal salts.

Although the compound of the present invention may be present as variousstereoisomers because it has an asymmetric carbon atom in its molecule,it is needless to say that the present invention includes all of theisomers and mixtures of them.

Further, although some of the compounds according to the presentinvention are present as hydrates, it is needless to say that thepresent invention includes such hydrates.

Representative processes for the preparation of the compound accordingto the present invention will now be described, though the compound canbe prepared by various processes. ##STR17##

A ketocarboxylic acid represented by the general formula (II) is reactedwith a Grignard reagent (MgX--CHR⁵ R⁶) or a lithium reagent (LiCHR⁵ R⁶)(wherein R⁵ and R⁶ are each as defined above and X represents Cl, Br orI) to give an alcohol (III). The solvent usable in this reactionincludes ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, dimethoxyethane and 1,4-dioxane; benzene, toluene andhexane. The reaction temperature may range from -78° C. to the boilingpoint of the solvent used, preferably from about -40° and 30° C.

Then, the alcohol (III) can be converted into an objective compound (I')through dehydration in the presence of an acid. When R⁵ is not ahydrogen atom and R⁶ is a hydrogen atom, the dehydration gives a Zisomer preferentially, while when R¹ is a group removable with acid,such as a methoxymethyl group, an objective compound (I') wherein R¹ isa hydrogen atom simultaneously can be prepared. The solvent to be usedin the dehydration includes ethers such as diethyl ether,tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; benzene, toluene,xylene and dichlorobenzene. The acid to be used therein includeshydrochloric acid, sulfuric acid, p-toluenesulfonic acid,D-10-camphorsulfonic acid, methanesulfonic acid, borontrifluoride-diethyl ether complex, trifluoroacetic acid, oxalic acid andphosphoric acid. The reaction temperature may range from -40° C. to theboiling point of the solvent used, preferably from room temperature tothe boiling point of the solvent used. ##STR18##

A ketoester represented by the general formula (IV) is reacted with aphosphorus compound represented by the general formula (VII), (VIII) or(IX) through Wittig reaction to give a compound (V). This reaction givesan (E) isomer preferentially when R⁵ is a hydrogen atom and R⁶ is not ahydrogen atom. When R⁵ and R⁶ are each a chlorine atom, the abovereaction is conducted by the use of triphenylphosphine and carbontetrachloride. When the reaction is conducted in the presence of a base,preferable results are obtained. The base usable therein includes sodiumhydride, potassium hydride, sodium amide, sodium methoxide, sodiumethoxide, potassium t-butoxide, methyllithium and n-butyllithium. Thereaction is conducted in the absence or presence of a solvent and thesolvent includes alcohols such as methanol and ethanol; benzene,toluene, diethyl ether, tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, N,N-dimethylformamide, acetonitrile and dimethylsulfoxide. The reaction temperature may range from -40° C. to theboiling point of the solvent used, preferably from about 0° to 100° C.

Then, the compound (V) is hydrolyzed with a base to give a carboxylicacid (VI). The base usable in this hydrolysis includes alkali metalcarbonates such as sodium carbonate and potassium carbonate; and alkalimetal hydroxides such as sodium hydroxide and potassium hydroxide. Thesolvent to be used therein may be suitably selected from among water,methanol, ethanol, tetrahydrofuran, acetonitrile, dimethyl sulfoxide andacetone. The reaction temperature ranges from about 0° C. to the boilingpoint of the solvent used.

When R¹ is a group easily removable with acid, such as a methoxymethylgroup, a compound (I') can be prepared from the compound (VI) by aconventional process. The solvent to be used in the deblocking may besuitably selected from among water, methanol, ethanol, diethylether,tetrahydrofuran, 1,4-dioxane, acetonitrile, acetone, benzene andtoluene. The acid to be used therein includes hydrochloric acid,sulfuric acid, p-toluenesulfonic acid, D-10-camphorsulfonic acid,methanesulfonic acid, trifluoroacetic acid, acetic acid, borontrifluoride-ether complex, oxalic acid, phosphoric acid and so on. Thereaction temperature may range from -40° C. to the boiling point of thesolvent used, preferably from room temperature to the boiling point ofthe solvent used.

Preparation process C

A compound represented by the formula (I) wherein Z is an ═NOR⁷ groupcan be prepared by the following process: ##STR19##

A ketoester represented by the general formula (IV) is reacted with anO-alkylhydroxylamine or a salt thereof in the presence of a base to givea compound (X) as a mixture of syn- and anti-isomers. The solvent to beused in this reaction may be suitably selected from among water,methanol, ethanol, tetrahydrofuran, 1,4-dioxane and dimethyl sulfoxide.The base usable therein includes alkali metal carbonates such as sodiumcarbonate and potassium carbonate; and alkali metal hydroxides such assodium hydroxide and potassium hydroxide. The reaction temperatureranges from 0° C. to the boiling point of the solvent used.

Then, the compound (X) can be converted into a carboxylic acid accordingto a conventional process (similar to the one described in thePreparation process B for the conversion of (V) into (VI)). In thisstep, a syn-isomer (XI) and an anti-isomer (XII) can be separated fromeach other to give purified isomers.

When R¹ is a group easily removable with acid, such as a methoxymethylgroup, a syn-naphthol (XIII) can be prepared from a syn-carboxylic acid(XI) according to a conventional process (similar to the one describedin the Preparation process B for the conversion of (VI) into (I')).

On the other hand, an anti-naphthol (XIV) can be prepared from ananti-carboxylic acid (XII) by the action of trifluoroacetic acid withoutcausing isomerization.

The solvent usable in this reaction includes dichloromethane,1,2-dichloroethane, diethyl ether, tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, benzene, toluene and so on. The reactiontemperature ranges from 0° C. to the boiling point of the solvent used.

Preparation process D

A compound represented by the general formula (I) wherein R² is an acylor branched alkyl group can be prepared by the following process:##STR20##

A compound (XV) which can be prepared by the Preparation process A canbe converted into an ester (XVI) according to a conventional process.

The ester (XVI) is reacted with an orthoester derivative such as methylorthoformate and ethyl orthoformate or dichloromethyl methyl ether inthe presence of a Lewis acid to give a formyl derivative (XVII). TheLewis acid usable in this step includes aluminum chloride, titaniumtetrachloride and zinc chloride. The solvent to be used therein includesdichloromethane and chloroform. The reaction temperature may range from-40° C. to the boiling point of the solvent used, preferably from -10°to 40° C.

Then, the formyl derivative (XVII) is reacted with boron tribromide togive a naphthol derivative (XVIII). The solvent to be used in thisreaction includes dichloromethane and chloroform and the reactiontemperature ranges from -40° C. to room temperature.

The naphthol derivative (XVIII) is reacted with chloromethyl methylether in the presence of a base to give a methoxymethyl ether (XIX). Thebase to be used in this reaction includes triethylamine,N,N-diisopropylethylamine, sodium hydride, potassium tert-butoxidepotassium carbonate and so on. The solvent to be used therein includesdichloromethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,N,N-dimethylformamide acetone and so on. The reaction temperature mayrange from -78° C. to the boiling point of the solvent used, preferablyfrom -40° C. to room temperature.

Then, the compound (XIX) is reacted with an alkyllithium reagent or aGrignard reagent to give a secondary alcohol (XX). The solvent usable inthis reaction includes diethylether, tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, hexane, benzene, toluene and so on, and thereaction temperature ranges from -78° C. to room temperature.

The alcohol (XX) is oxidized into an acyl derivative represented by thegeneral formula (XXI) by a conventional process. The oxidizing agentusable in this step includes manganese dioxide, pyridinium dichromateand so on. The reaction solvent includes acetone, diethylether,acetonitrile, benzene, toluene, dichloromethane, chloroform,N,N-dimethylformamide and so on. The reaction temperature may besuitably selected within a range of from the temperature attained undercooling with ice to the boiling point of the solvent used.

The acyl derivative (XXI) can be hydrolyzed with an alkali and freed ofthe protective group in a similar manner to the one described in thePreparation process B for the conversion of (V) through (VI) into (I')to give a carboxylic acid represented by the general formula (XXIII).

Alternatively, the acyl derivative (XXI) is reacted with a phosphoruscompound represented by the general formula (VII), (VIII) or (IX)wherein R⁵ and R⁶ are each a hydrogen atom through Wittig reactionaccording to a conventional process to give a compound (XXIV). Thesolvent, temperature and base to be employed in this reaction are eachas described in the Preparation process B for the conversion of (IV)into (V).

The compound (XXIV) is catalytically reduced into a compound (XXV) in ahydrogen atmosphere of about 1 atm according to a conventional process.The catalyst to be used in this reduction includes palladium-carbon,platinum oxide, Raney nickel and so on. The solvent to be used thereinmay be suitably selected from among water, methanol, ethanol, propanol,ethyl acetate, tetrahydrofuran, 1,4-dioxane and acetic acid. Thereaction mixture ranges from 0° C. to room temperature.

Further, the compound (XXV) is converted into a carboxylic acidrepresented by the general formula (XXVII) in a similar manner to thatdescribed in the Preparation process B for the conversion of (V) through(VI) into (I').

Preparation process E

A compound represented by the general formula (I) or (XIII) wherein R¹is an acyl group can be prepared by the following process: ##STR21##

That is, a compound (XXVIII) is reacted with chloromethyl methyl etherin the presence of a base to give a methoxymethyl ester (XXIX). The baseusable in this reaction includes triethylamine,N,N-diisopropylethylamine, potassium carbonate and so on, while thesolvent usable therein includes dichloromethane, chloroform,diethylether, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide,acetone and so on. The reaction is conducted at a temperature rangingfrom -40' C. to the boiling point of the solvent used, preferably undercooling with ice.

Then, the methoxymethyl ester (XXIX) is reacted with an acyl chloride inthe presence of a base to give a compound (XXX). The base usable in thisstep includes triethylamine, N,N-diisopropylethylamine, sodium hydride,potassium tert-butoxide and so on, while the solvent to be used thereinmay be suitably selected from among dichloromethane, chloroform,diethylether, 1,4-dioxane, 1,2-dimethoxyethane andN,N-dimethylformamide. The reaction may be conducted at a temperatureranging from -40° C. to room temperature, preferably under cooling withice.

The compound (XXX) can be easily converted into a compound (XXXI)through deblocking in a similar manner to the one described in thePreparation process B for the conversion of (VI) into (I').

Preparation Process for Starting Material: A

Among the compounds represented by the general formula (II) or (IV)which are each used as a starting material in the above-mentionedPreparation process A, B or C, a compound wherein R² is a lower alkoxygroup, a lower branched alkoxy group or a cyloalkoxy group can beprepared by, for example, the following process: ##STR22##

That is, a known compound (XXXII) [see R. J. Packer et al., J. Chem.Soc., (C), 2194(1967)] is reduced with hydrazine or hydrazine hydrateand sodium hydroxide to give a naphthol derivative (XXXIII). In thisstep, a semicarbazone can be used instead of hydrazine and potassiumhydroxide or sodium ethoxide can be used instead of sodium hydroxide.The solvent usable in this reduction includes diethylene glycol,triethanolamine and so on, and the reaction temperature ranges from 80°C. to the boiling point of the solvent used.

The naphthol derivative (XXXIII) is reacted with chloromethyl methylether in the presence of a base to give a methoxymethyl ether (XXXIV).The base usable in this reaction includes triethylamine,N,N-diisopropylethylamine, sodium hydride, potassium tert-butoxide,potassium carbonate and so on. The solvent to be used therein incudesdichloromethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,N,N-dimethylformamide, acetone and so on. The reaction temperature mayrange from -78° C. to the boiling point of the solvent used, preferablyfrom -40° C. to room temperature.

The methoxymethyl ether (XXXIV) is reacted with a strong base such asn-butyllithium and then with N,N-dimethylformamide to give an aldehyde(XXXV). The reactions are conducted in an etheric solvent such as etherand tetrahydrofuran at a temperature ranging from -78° to 30° C.,preferably from -30° C. to room temperature.

The aldehyde (XXXV) can be oxidized with hydrogen peroxide, or a peracidsuch as peracetic acid and m-chloroperbenzoic acid to give a formate(XXXVI). The solvent to be used in this oxidation may be suitablyselected from among water, dichloromethane, chloroform, acetic acid andso on.

The formate (XXXVI) can be hydrolyzed with an alkali according to aconventional process to give a 2-naphthol derivative (XXXVII).

The naphthol derivative (XXXVII) is reacted with an alkyl halide or asulfonate ester in the presence of a base, for example, an alkali metalcarbonate such as sodium carbonate and potassium carbonate or an alkalimetal hydride such as sodium hydride. The halogen constituting the alkylhalide includes chlorine, bromine and iodine. The solvent to be used inthis step includes ketones such as acetone and methyl ethyl ketone;N,N-dimethylformamide, dimethyl sulfoxide and tetrahydrofuran.

The obtained alkoxynaphthalene (XXXVIII) can be deblocked withhydrochloric acid, sulfuric acid or p-toluenesulfonic acid by aconventional process to give a 1-naphthol derivative (XXXIX).

The naphthol derivative (XXXIX) is reacted with ethyloxalyl chloride,ethylmalonyl chloride or ethylsuccinyl chloride to give a ketoesterrepresented by the general formula (XXXX). The catalyst to be used inthis reaction includes aluminum chloride, titanium tetrachloride, zincchloride and so on. The solvent to be used therein includesdichloromethane, chloroform, benzene, toluene and so on.

The ketoester (XXXX) is reacted with chloromethyl methyl ether in thepresence of a base such as triethylamine, N,N-diisopropylethylamine,sodium hydride and potassium carbonate by a conventional process to givea methoxymethyl derivative represented by the general formula (XXXXI).The solvent usable in this reaction is one inert to the reaction, forexample dichloromethane, chloroform, diethylether, tetrahydrofuran,N,N-dimethylformamide or acetone. The reaction temperature may rangefrom -40° C. to the boiling point of the solvent used, preferably fromabout 0° C. to room temperature.

The obtained ester (XXXXI) can be hydrolyzed with a base such as sodiumhydroxide and potassium hydroxide by a conventional process to give acarboxylic acid (XXXXII). The solvent to be used in this hydrolysis maybe suitably selected from among water, ethanol, methanol,tetrahydrofuran, dimethyl sulfoxide and so on. The reaction temperaturemay range from -40° to 80° C., preferably from about 0° C. to roomtemperature.

Preparation process for starting material: B

Among the compounds represented by the general formula (II) or (IV)which are each used as a starting material in the above-mentionedPreparation process A, B or C, a compound wherein R² is a lower alkylgroup can be prepared from a compound (XXXIV) which can be prepared bythe above-mentioned Preparation process A for starting material by thefollowing process: ##STR23##

That is, a compound (XXXIV) is reacted with n-butyllithium and then withan alkyl halide in the presence of tetramethylethylenediamine to give analkylate (XXXXIII). The reaction is conducted in an etheric solvent suchas ether and tetrahydrofuran at a temperature ranging from -78° to 30°C., preferably from -30 to room temperature.

The preparation of a compound (XXXXVII) from the alkylate (XXXIII) canbe conducted in a similar manner to that described in theabove-mentioned Preparation process A for starting material.

Preparation process for starting compound: C

The compound used in the above-mentioned Preparation process D can beprepared by the following process: ##STR24##

That is, a methoxy derivative (XXXXVIII) can be prepared by reacting anaphthol derivative (XXXIII) which can be prepared by theabove-mentioned Preparation process A for starting material with methyiodide in the presence of a base. The base usable in this reactionincludes alkali metal carbonates such as sodium carbonate and potassiumcarbonate; triethylamine, N,N-diisopropylethylamine, sodium hydride andpotassium tert-butoxide. The solvent to be used therein includesacetone, methyl ethyl ketone, tetrahydrofuran, N,N-dimethylformamide,dimethyl sulfoxide, dichloromethane, chloroform and so on.

The preparation of a compound (XXXXX) from the methoxy derivative(XXXXVIII) can be conducted in a similar manner to that described in thePreparation process A for starting material A.

The conversion of the compound (XXXXX) into a compound (XV) can beconducted in a similar manner to that described in the Preparationprocess A.

In the present invention, the intermediates (naphthalene derivatives)defined by the following general formula (A) are novel compounds.##STR25## wherein R^(a) means a benzyl group, R^(b) stands for ahydrogen atom or a lower alkyl group, R^(c) stands for a hydrogen atomor a lower alkyl group and R^(d) represents a hydrogen atom or a grouprepresented by the formula: ##STR26## (wherein R^(e) stands for ahydroxyl group or a lower alkyl group).

Among these naphthalene derivatives, the compounds defined by thefollowing formulae are important as intermediate, which will beexplained in the referencial examples 1, 12 and 22, to prepare thecompounds in the present invention. ##STR27##

EXAMPLES

Pharmacological Experimental Examples will now be described in order toillustrate the effects of the present invention.

EXPERIMENTAL EXAMPLES Activity against the PGE₂ production from culturedsynovial cell of rat

A synovial membrane taken out of the knee joint of a Lewis male rat wastreated with collagenase-trypsin to separate off synovial cells. A testcompound was added to a system prepared by the subculture of thesynovial cells. The cells were stimulated with a neutrophil-originatingfactor (IL-1-like factor) to induce PGE₂ production. After one day, theamount of PGE₂ liberated into the culture medium was determined byradioimmunoassay (see R. Hashida et al., Prostaglandins, 27 (1984),697).

Activity against LTB₄ production from human neutrophil

A test compound was added to a suspension of neutrophil separated fromthe human peripheral blood and the obtained mixture was preincubated at37° C. for 5 minutes, followed by the addition of calcium ionophoreA23187 in an amount of 2 μg/ml. After 10 minutes, the obtained mixturewas cooled to stop the reaction. The amount of LTB₄ contained in thesupernatant of the reaction mixture was determined by radioimmunoassay(see H. Shirota et al., Arzneim Forsol Drug Res., 37 (1987) 930).

The representative results of the experiment are given in Table 1.

                  TABLE 1                                                         ______________________________________                                               Inhibitory activity against                                                                    Inhibitory activity against                                  PGE.sub.2 production                                                                           LTB.sub.4 production                                  Example                                                                              from synovial cells of rat                                                                     from human neutrophil                                 No.    IC.sub.50 (μM)                                                                              IC.sub.50 (μM)                                     ______________________________________                                         1     0.42             0.51                                                   2     0.62             0.32                                                   3     1.45             0.52                                                   4     2.76             1.68                                                   5     1.64             0.51                                                   7     3.10             >10                                                   10     2.10             1.86                                                  11     1.88             1.09                                                  12     3.54             10                                                    13     3.35             0.83                                                  14     3.23             0.72                                                  15     1.07             0.73                                                  40     2.04             3.16                                                  55     0.28             2.35                                                  ______________________________________                                    

It can be understood from the results that the compound of the presentinvention has an inhibitory activity against the production of twomediators, i.e., prostaglandin (PG) and leukotriene (LT).

With respect to inflammatory reactions, it is known that PGE₂ producedby the arachidonate cascade is a main substance causative of pyrexia,sore, swelling and other symptoms and it is also well known that theanti-inflammatory mechanism of many current nonsteroidalanti-inflammatory drugs resides mainly in the inhibition ofcycloxygenase.

On the other hand, a lipoxygenase system is believed to participatesignificantly in inflammation, because LTB₄ causes the migration,aggregation, adherence and/or degranulation of leukocyte and LTC₄ and D₄enhance the permeability of vessel. It has been clinically ascertainedthat the LTB₄ concentration in the synovial fluid of a patient withrheumatoid arthritis is high and the 5-lipoxygenase activity of thearticular tissues of such a patient is extremely high (see F. Hirata etal., Proc. Natl. Acad. Sci., 78 (1981) 3190).

Accordingly, the compounds of the present invention characterized bybeing capable of inhibiting LT production at a concentration capable ofinhibiting PG production is extremely useful as an anti-inflammatorydrug.

That is, the compounds of the present invention are efficacious not onlyin the resolution and pain-killing of chronic rheumatoid arthritis,osteoarthritis, shoulder periarthritis, cervicobrachial syndrome,lumbago and so on and postoperative and posttraumatic resolution andpain-killing, but also in the treatment of inflammation in which LTparticipates.

In addition, the compounds of the present invention are effective intreating diseases for which the above-mentioned inhibitory activityagainst the production of prostaglandin (PG) and leukotriene (LT) isefficacious.

When the compounds of the present invention are used as therapeutic andpreventive agents for these diseases, they may be each administeredorally as a tablet, powder, granule, capsule or syrup, or parenterallyas a suppository, injection, external preparation or drop. Oraladministration is preferable.

The dose of the compound remarkably varies depending upon the kind andsymptom of disease and the age of a patient. When it is orallyadministered to a human being, it is 0.01 to 20 mg/kg, preferably 0.1 to15 mg/kg, still preferably 1 to 10 mg/kg, which may be administered in 1to 3 portions a day.

The compounds of the present invention can be each converted into a drugfor oral or parenteral administration by the use of a conventionalpharmacologically acceptable carrier according to a conventionalprocess.

An injection or drop according to the present invention is prepared byadding a pH modifier, buffer, stabilizer and/or solubilizing agent atneed to an active ingredient, followed by freeze drying at need, andconverting the obtained mixture into a subcutaneous, intramuscular orintravenous injection or a drop by a conventional process.

EXAMPLE

Examples will now be described in order to illustrate the compounds ofthe present invention and the process for the preparation thereof inmore detail, though the present invention is not limited to them.

The preparation of the starting compounds used in Examples will bedescribed in Referential Examples.

In the Referential Examples and Examples which follow, Me stands for amethyl group, Et an ethyl group and Ac an acetyl group.

note 1) in some cases, no peak assignable to carboxylic acid wasdetected in nuclear magnetic resonance spectroscopy.

note 2) each melting point was determined with a micro melting pointapparatus (mfd. by Yanagimoto Seisakusho).

REFERENTIAL EXAMPLE 1 ##STR28##

122 g of 8-benzoyl-1-naphthol was suspended in 800 ml of diethyleneglycol, followed by the addition of 250 ml of hydrazine monohydrate and99 g of sodium hydroxide at room temperature. The obtained mixture wasstirred at 100° C. for 48 hours and cooled to room temperature byallowing to stand, followed by the addition of 500 ml of water. Theobtained mixture was acidified with concentrated hydrochloric acid andextracted with 1.5 l of toluene. The organic layer was washed with asaturated aqueous solution of sodium chloride and purified by silica gelcolumn chromatography (developer: benzene) to give 100 g of the titlecompound as a pale-yellow crystal.

m.p.: 67° to 71° C.

¹ H-NMR (90 MHz, CDCl₃) δ: 4.67 (s, 2H), 5.08 (s, 1H), 6.54 (dd, J=7.2Hz, 1.4 Hz, 1H), 6.80˜7.50 (m, 9H), 7.61 (dd, J=7.2 Hz, 1.4 Hz, 1H).##STR29##

100 g of 8-benzyl-1-naphthol was dissolved in 300 ml ofN,N-dimethylformamide to give a solution. 18.6 g of sodium hydride (55%suspension in oil) was added to the solution under cooling with ice.After 30 minutes, 34.4 g of chloromethyl methyl ether was added to theobtained mixture under cooling with ice, followed by stirring for 10minutes. The obtained mixture was further stirred at room temperaturefor 30 minutes. The resulting reaction mixture was poured onto ice-waterand the obtained mixture was extracted with 1.2 l of ethyl acetate. Theorganic layer was washed with a saturated aqueous solution of sodiumchloride, dried over anhydrous magnesium sulfate and concentrated in avacuum. The obtained residue was purified by silica gel columnchromatography (developer: hexane to 9% ethyl acetate/hexane) to give103 g of the title compound as a yellow oil.

¹ H-NMR (90 MHz, CDCl₃) δ: 3.11 (s, 3H), 4.65 (br s, 2H), 4.96 (s, 2H),6.8˜7.55 (m, 10H), 7.65 (dd, J=7.2 Hz, 1.8 Hz, 1H). ##STR30##

103 g of 8-benzyl-1-methokymethoxynaphthalene was dissolved in 300 ml ofanhydrous ether to give a solution. 190 ml of a 2.5M n-butyllithiumsolution (in hexane) was dropped into the solution under cooling withice in a nitrogen atmosphere. The obtained mixture was stirred at roomtemperature for 2 hours and cooled to -40° C., followed by the dropwiseaddition of 44 ml of anhydrous N,N-dimethylformamide. The temperature ofthe reaction mixture was raised again to room temperature, followed bythe addition of 100 ml of water. The obtained mixture was extracted withethyl acetate. The organic layer was washed with water, dried overanhydrous magnesium sulfate and concentrated in a vacuum. The residuewas purified by silica gel column chromatography (developer: 5 to 20%ethyl acetate/hexane) to give 110 g of the title compound as a yellowoil.

¹ H-NMR (90 MHz, CDCl₃) δ: 3.44 (s, 3H), 4.70 (br s, 2H), 4.82 (s, 2H),6.85˜7.80 (m, 9H), 7.80 (d, J=7.9 Hz, 1H), 10.10 (br s, 1H). ##STR31##

96 g of 8-benzyl-1-methoxymethoxy-2-naphthaldehyde was dissolved in 500ml of dichloromethane to give a solution. 76.4 g of 85%m-chloroperbenzoic acid was gradually added to the solution at roomtemperature. The obtained reaction mixture was heated under reflux forone hour, cooled by allowing to stand and further cooled with ice. Theresulting mixture was filtered to remove insolubles. The filtrate waswashed with an aqueous solution of sodium thiosulfate, a saturatedaqueous solution of sodium hydrogen-carbonate and a saturated aqueoussolution of sodium chloride successively, dried over anhydrous magnesiumsulfate and concentrated in a vacuum. The obtained residue was used inthe subsequent reaction without being purified. ##STR32##

The formate prepared in the step (d) was dissolved in 300 ml ofmethanol, followed by the addition of 43 g of potassium carbonate. Theobtained mixture was stirred at room temperature for 30 minutes andfiltered to remove insolubles. The filtrate was concentrated in avacuum. 400 ml of water was added to the residue. The obtained mixturewas neutralized with concentrated hydrochloric acid and extracted withethyl acetate. The organic layer was washed with water twice, dried overanhydrous magnesium sulfate and concentrated in a vacuum to give a brownoil. The oil was purified by silica gel column chromatography(developer: 5% ethyl acetate/hexane) to give 63 g of the title compoundas a colorless crystal.

m.p.: 54° to 57.5° C.

¹ H-NMR (400 MHz, CDCl₃) δ: 3.54 (s, 3H), 4.47 (s, 2H), 4.66 (s, 2H),7.06 (br d, J=7.3 Hz, 2H), 7.16 (br t, J=7.3 Hz, 1H), 7.20 (dd, J=7.9Hz, 1.5Hz, 1H), 7.20˜7.30 (m, 1H), 7.22 (d, J=8.8 Hz, 1H), 7.25 (br t,J=7.3 Hz, 2H), 7.58 (d, J=8.8 Hz, 1H), 7.68 (dd, J=7.9 Hz, 1.5 Hz, 1H),8.16 (s, 1H). ##STR33##

82.7 g of 8-benzyl-1-methoxymethoxy-2-naphthol was dissolved in 300 mlof N,N-dimethylformamide to give a solution. 12.3 g of sodium hydride(55% suspension in oil) was added to the solution at room temperature.The obtained mixture was stirred for 30 minutes, followed by thedropwise addition of 17.5 ml of methyl iodide. The obtained mixture wasstirred for one hour and poured onto ice-water. The obtained mixture wasextracted with ethyl acetate. The organic layer was washed with asaturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate and concentrated in a vacuum. The obtained residue waspurified by silica gel column chromatography (developer: 3 to 9% ethylacetate/hexane) to give 79.5 g of the title compound as a yellow oil.

¹ H-NMR (400 MHz, CDCl₃) δ: 3.50 (s, 3H), 3.94 (s, 3H), 4.82 (s, 2H),5.10 (s, 2H), 7.10˜7.40 (m, 8H), 7.55˜7.65 (m, 2H). ##STR34##

79.5 g of 8-benzyl-2-methoxy-1-methoxymethoxynaphthalene was dissolvedin 300 ml of acetone to give a solution. 120 ml of 6N hydrochloric acidwas added to the solution at room temperature. The obtained mixture wasstirred for 1.5 hours, followed by the addition of 400 ml of water. Theobtained mixture was extracted with ethyl acetate. The organic layer waswashed with water, dried over anhydrous magnesium sulfate and distilledin a vacuum to remove the solvent. The obtained solid was washed withhexane/diisopropyl ether (1:1) to give 51 g of the title compound as acolorless crystal.

m.p.: 84° to 86° C.

¹ H-NMR (400 MHz, CDCl₃) δ: 3.95 (s, 3H), 4.77 (br s, 2H), 6.25 (s, 1H),7.20˜7.60 (m, 8H), 7.39 (d, J=9.0 Hz, 1H), 7.62 (br d, J=8.0 Hz, 1H).

REFERENTIAL EXAMPLES 2 TO 5

The following compounds were each prepared in a similar manner to thatof the Referential Example 1 except that the methyl iodide used in thestep (f) was replaced by ethyl iodide, propyl iodide, isopropyl iodideor bromocyclopentane:

8-benzyl-2-ethoxy-1-naphthol

8-benzyl-2-propoxy-1-naphthol

8-benzyl-2-isopropoxy-1-naphthol

8-benzyl-2-cyclopentyloxy-1-naphthol.

REFERENTIAL EXAMPLE 6 ##STR35##

10 g of 8-benzyl-1-methoxymethoxynaphthalene was dissolved in 100 ml ofanhydrous ether, followed by the addition of 6.5 ml oftetramethylethylenediamine. 27 ml of a 1.6M solution of n-butyllithiumin hexane was dropped into the obtained mixture under cooling with ice.The obtained mixture was stirred at 0° C. for one hour, followed by thedropwise addition of 2.7 ml of methyl iodide. The obtained mixture wasstirred at room temperature for one hour and poured into a saturatedaqueous solution of ammonium chloride. The obtained mixture wasextracted with ethyl acetate. The organic layer was dried over anhydrousmagneisum sulfate and distilled in a vacuum to remove the solvent. Theresidue was dissolved in 150 ml of acetone, followed by the addition of60 ml of 6N hydrochloric acid. The obtained mixture was stirred at roomtemperature for one hour, followed by the addition of water. Theobtained mixture was extracted with ethyl acetate. The organic layer wasdried over anhydrous magnesium sulfate and distilled in a vacuum toremove the solvent. The residue was purified by silica gel columnchromatography (developer: 3% ethyl acetate/hexane) to give 6 g of thetitle compound as a yellow oil.

¹ H-NMR (400 MHz, CDCl₃) δ: 2.31 (s, 3H), 4.64 (s, 2H), 5.00 (s, 1H),7.05˜7.32 (m, 7H), 7.33 (t, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.68(d, J=8.0 Hz, 1H).

REFERENTIAL EXAMPLES 7 TO 9

The following compounds were each prepared in a similar manner to thatof the Referential Example 6 except that the methyl iodide was replacedby ethyl iodide, propyl iodide or butyl iodide:

8-benzyl-2-ethyl-1-naphthol

8-benzyl-2-propyl-1-naphthol

8-benzyl-2-butyl-1-naphthol.

REFERENTIAL EXAMPLE 10 ##STR36##

100 g of 8-benzyl-1-naphthol was dissolved in 300 ml ofN,N-dimethylformamide to give a solution. 24.2 g of sodium hydride (55%suspension in oil) was added to the solution under cooling with ice. Theobtained mixture was stirred at room temperature for 30 minutes. Methyliodide was added to the resulting mixture under cooling with ice. Theobtained mixture was stirred for 30 minutes under cooling with ice andpoured onto ice-water. The obtained mixture was extracted with ethylacetate. The organic layer was washed with a saturated aqueous solutionof sodium chloride twice, dried over anhydrous magnesium sulfate anddistilled in a vacuum to remove the solvent. The residue was purified bysilica gel column chromatography (developer: 5% ethyl acetate/hexane) togive 73 g of the title compound.

¹ H-NMR (400 MHz, CDCl₃) δ: 3.70 (s, 3H), 4.69 (s, 2H), 6.76 (d, J=8.0Hz, 1H), 7.08 (d, J=8.0 Hz, 2H), 7.10˜7.28 (m, 4H), 7.37 (t, J=8.0 HZ,1H), 7.37 (t, J=8.0 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.0 Hz,1H).

REFERENTIAL EXAMPLE 11 ##STR37##

The title compound was prepared from 8-pentanoyl-1-naphthol in a similarmanner to that of the Referential Example 1.

REFERENTIAL EXAMPLE 12 ##STR38##

64 g of anhydrous aluminum chloride was suspended in 500 ml ofdichloromethane. 40.3 ml of ethyloxalyl chloride was added to thesuspension at room temperature. A solution of 63.4 g of8-benzyl-2-methoxy-1-naphthol in 300 ml of dichloromethane was droppedinto the obtained mixture under cooling with ice. The obtained mixturewas stirred for 30 minutes under cooling with ice and poured onto 1 l ofice-water. The organic layer was washed with water, dried over anhydrousmagnesium sulfate and distilled in a vacuum to remove the solvent. Theobtained solid was washed with diisopropyl ether to give 54 g of thetitle compound as a yellow crystal.

m.p.: 124 ° to 126° C.

¹ H-NMR (400 MHz, CDCl₃) δ1.44 (t, J=7.1 Hz, 3H), 3.98 (s, 3H), 4.47 (q,J=7.1 Hz, 2H), 4.76 (s, 2H), 7.00 (s, 1H), 7.09 (br d, J=8.2 Hz, 2H),7.15 (br t, J=8.2 Hz, 1H), 7.24 (br t, J=8.2 Hz, 2H), 7.30 (dd, J=7.0Hz, 1.1 Hz, 1H), 7.51 (dd, J=8.8 Hz, 7.0 Hz, 1H), 7.74 (s, 1H), 9.03(dd, J=8.8 Hz, 1.1 Hz, 1H). ##STR39##

5.0 g of the naphthol prepared in the step (a) was dissolved in 100 mlof dichloromethane to give a solution. 7.4 ml ofN,N-diisopropylethylamine and 2.2 ml of chloromethyl methyl ether wereadded to the solution successively at room temperature. The obtainedmixture was stirred for 30 minutes and washed with dilute hydrochlopicacid, water, a saturated aqueous solution of sodium hydrogencarbonateand water successively. The organic layer was dried over anhydrousmagnesium sulfate and distilled in a vacuum to remove the solvent. 5.2 gof the title compound was obtained as a yellow crystal.

m.p.: 70° to 72° C.

¹ H-NMR (400 MHz, CDCl₃) δ: 1.44 (t, J=7.1 Hz, 3H), 3.38 (s, 3H), 3.92(s, 3H), 4.48 (q, J=7.1 Hz, 2H), 4.80 (br s, 2H), 5.20 (s, 2H), 7.09 (brd, J=7.5 Hz, 2H), 7.16 (br t, J=7.5 Hz, 1H), 7.24 (br t, J=7.5 Hz, 2H),7.28 (dd, J=7.1 Hz, 1.1 Hz, 1H), 7.46 (dd, J=8.8 Hz, 7.1 Hz, 1H), 7.77(s, 1H), 8.86 (dd, J=8.8 Hz, 1.1 Hz, 1H).

REFERENTIAL EXAMPLES 13 TO 21

The following compounds were prepared respectively from the compoundsprepared in the Referential Examples 2 to 9 and 11 in a similar mannerto that of the Referential Example 12:

ethyl 2-(5-benzyl-3-ethoxy-4-methoxymethoxy-1-naphthyl)-2-oxo-acetate

ethyl 2-(5-benzyl-4-methoxymethoxy-3-propoxy-1-naphthyl)-2-oxo-acetate

ethyl2-(5-benzyl-3-isopropoxy-4-methoxymethoxy-1-naphthyl)-2-oxo-acetate

ethyl2-(5-benzyl-3-cyclopentyloxy-4-methoxymethoxy-1-naphthyl)-2-oxo-acetate

ethyl 2-(5-benzyl-4-methoxymethoxy-3-methyl-1-naphthyl)-2-oxo-acetate

ethyl 2-(5-benzyl-3-ethyl-4-methoxymethoxy-1-naphthyl)-2-oxo-acetate

ethyl 2-(5-benzyl-4-methoxymethoxy-3-propyl-1-naphthyl)-2-oxo-acetate

ethyl 2-(5-benzyl-3-butyl-4-methoxymethoxy-1-naphthyl)-2-oxo-acetate

ethyl 2-(3-methoxy-1-methoxymethoxy-5-pentyl-1-naphthyl)-2-oxo-acetate.

REFERENTIAL EXAMPLE 22 ##STR40##

46.6 g of anhydrous aluminum chloride was suspended in 400 ml ofdichloromethane and the obtained suspension was stirred under coolingwith ice, followed by the dropwise addition of a solution of 49.6 g of8-benzyl-1-methoxynaphthalene and 31.2 g of ethyloxalyl chloride in 500ml of dichloromethane. After the completion of the dropwise addition,the obtained mixture was stirred under cooling with ice for 30 minutesand poured onto ice-water. The obtained mixture was extracted with ethylacetate. The organic layer was washed with a saturated aqueous solutionof sodium chloride twice, dried over anhydrous magnesium sulfate anddistilled in a vacuum to remove the solvent. The obtained residue waspurified by silica gel column chromatography (developer: 10 to 20% ethylacetate/hexane) to give 44 g of the title compound as a yellow crystal.

¹ H-NMR (400 MHz, CDCl₃) δ: 1.42 (t, J=7.2 Hz, 3H), 3.76 (s, 3H), 4.45(q, J=7.2 Hz, 2H), 4.66 (s, 2H), 6.74 (d, J=8.0 Hz, 1H), 7.01 (d, J=8.0Hz, 2H), 7.13 (t, J=8.0 Hz, 1H), 7.22 (t, J=8.0 Hz, 2H), 7.37 (d, J=8.0Hz, 1H), 7.62 (t, J=8.0 Hz, 1H), 7.88 (d, J=8.0 Hz, 1H), 9.21 (d, J=8.0Hz, 1H).

REFERENTIAL EXAMPLE 23 ##STR41##

The title compound was prepared in a similar manner to that of theReferential Example 12 except that ethylsuccinyl chloride was usedinstead of the ethyloxalyl chloride.

REFERENTIAL EXAMPLE 24 ##STR42##

4.5 g of anhydrous aluminum chloride was suspended in 200 ml ofdichloromethane. 3.6 ml of ethylmalonyl chloride was added to thesuspension at room temperature. A solution of 5.0 g of8-benzyl-2-methoxy-1-naphthol in 100 ml of dichloromethane was droppedinto the obtained mixture under cooling with ice. The obtained mixturewas stirred at room temperature for 8 hours and poured onto 1 l ofice-water. The organic layer was washed with water, dried over anhydrousmagnesium sulfate and concentrated in a vacuum. The residue was purifiedby silica gel column chromatography (developer: 16% ethylacetate/hexane) to give 2.64 g of the title compound as a deep-yellowoil. ##STR43##

2.64 g of the naphthol prepared in the step (a) was dissolved in 50 mlof dichloromethane to give a solution. 1.8 ml ofN,N-diisopropylethylamine and 0.7 ml of chloromethyl methyl ether wereadded to the solution successively. The obtained mixture was stirred atroom temperature for 30 minutes, washed with dilute hydrochloric acid,water, a saturated aqueous solution of sodium hydrogencarbonate andwater successively, dried over anhydrous magnesium sulfate and distilledin a vacuum to remove the solvent. The obtained residue was purified bysilica gel column chromatography (developer: 10% ethyl acetate/hexane)to give 1.92 g of the title compound as a yellow oil. ##STR44##

1.9 g of the methoxymethyl ether prepared in the step (b) was dissolvedin 50 ml of N,N-dimethylformamide to give a solution. 0.44 g of sodiumhydride (55% suspension in oil) was added to the solution at roomtemperature. The obtained mixture was stirred for 30 minutes, followedby the addition of 0.86 ml of methyl iodide. The obtained mixture wasstirred for one hour and poured onto ice-water. The obtained mixture wasextracted with ethyl acetate. The organic layer was washed with asaturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate and concentrated in a vacuum. The obtained residue waspurified by silica gel column chromatography (developer: 10% ethylacetate/hexane) to give 1.47 g of the title compound as a yellow oil.

¹ H-NMR (400 MHz, CDCl₃) δ: 0.96 (t, J=7.5 Hz, 3H), 1.58 (s, 6H), 3.43(s, 3H), 3.88 (s, 3H), 4.04 (q, J=7.5 Hz, 2H), 4.80 (s, 2H), 5.10 (s,2H), 7.06˜7.14 (m, 8H), 7.78 (br d, J=8.5 Hz, 1H).

REFERENTIAL EXAMPLES 25 TO 28

The following compounds were each prepared in a similar manner to thatdescribed in the Referential Examples 1 and 12:

ethyl2-[5-(p-chlorobenzyl)-3-methoxy-4-methoxymethoxy-1-naphthyl]-2-oxo-acetate

ethyl2-[3-methoxy-5-(p-methoxybenzyl)-4-methoxymethoxy-1-naphthyl]-2-oxo-acetat

ethyl2-[3-methoxy-4-methoxymethoxy-5-(p-methylbenzyl)-1-naphthyl]-2-oxo-acetate

ethyl2-[3-methoxy-5-(o-methoxybenzyl)-4-methoxymethoxy-1-naphthyl]-2-oxo-acetate.

REFERENTIAL EXAMPLE 29 ##STR45##

3 g of the ester prepared in the Referential Example 12 was suspended in30 ml of ethanol, followed by the addition of 10 ml of water and 320 mgof sodium hydroxide. The obtained mixture was stirred at roomtemperature until the ester was dissolved completely, followed by theaddition of a saturated aqueous solution of ammonium chloride. The pH ofthe mixture was adjusted to 5 by the addition of 1N hydrochloric acid.The resulting mixture was extracted with ethyl acetate under saltingout. The organic layer was dried over anhydrous magnesium sulfate andfiltered. The filtrate was distilled to remove the solvent. The obtainedresidue was used as such as a starting compound. The residue wasrecrystallized from ethyl acetate/hexane to give 2.34 g of the titlecompound as a pale yellow crystal.

m.p.: 75° to 79° C.

¹ H-NMR (400 MHz, DMSO-d₆) δ: 3.35 (s, 3H), 3.83 (s, 3H), 4.71 (br s,2H), 5.13 (s, 2H), 7.02 (br d, J=7.7 Hz, 2H), 7.09 (br t, J=7.7 Hz, 1H),7.19 (br t, J=7.7 Hz, 2H), 7.21 (br s, 1H), 7.26 (dd, J=7.1 Hz, 1.2 Hz,1H), 7.34 (dd, J=8.6 Hz, 7.1 Hz, 1H), 7.88 (s, 1H), 8.71 (dd, J=8.6 Hz,1.2 Hz, 1H).

REFERENTIAL EXAMPLES 30 TO 41

The following compounds were prepared in a similar manner to that of theReferential Example 29 respectively from the compounds prepared in theReferential Examples 13 to 21 and 25 to 27:

2-(5-benzyl-3-ethoxy-4-methoxymethoxy-1-naphthyl)-2-oxo-acetic acid

2-(5-benzyl-4-methoxymethoxy-3-propoxy-1-naphthyl)-2-oxo-acetic acid

2-(5-benzyl-3-isopropoxy-4-methoxymethoxy-1-naphthyl)-2-oxo-acetic acid

2-(5-benzyl-3-cyclopentyloxy-4-methoxymethoxy-1-naphthyl)-2-oxo-aceticacid

2-(5-benzyl-4-methoxymethoxy-3-methyl-1-naphthyl)-2-oxo-acetic acid

2-(5-benzyl-3-ethyl-4-methoxymethoxy-1-naphthyl)-2-oxo-acetic acid

2-(5-benzyl-4-methoxymethoxy-3-propyl-1-naphthyl)-2-oxo-acetic acid

2-(5-benzyl-3-butyl-4-methoxymethoxy-1-naphthyl)-2-oxo-acetic acid

2-(3-methoxy-1-methoxymethoxy-5-pentyl-1-naphthyl)-2-oxo-acetic acid

2-[5-(p-chlorobenzyl)-3-methoxy-4-methoxymethoxy-1-naphthyl]-2-oxo-aceticacid

2-[3-methoxy-5-(p-methoxybenzyl)-4-methoxymethoxy-1-naphthyl]-2-oxo-aceticacid

2-[3-methoxy-4-methoxymethoxy-5-(p-methylbenzyl)-1-naphthyl]-2-oxo-aceticacid.

EXAMPLE 1 ##STR46##

3.0 g of the ketocarboxylic acid prepared in the Referential Example 29was dissolved in 50 ml of tetrahydrofuran to give a solution. 41 ml of a1M solution of ethylmagnesium bromide in tetrahydrofuran was droppedinto the solution in 5 minutes under cooling with ice. The obtainedmixture was stirred for one hour under cooling with ice and poured ontoice-water. The obtained mixture was made weakly acidic with dilutehydrochloric acid and extracted with ethyl acetate. The organic layerwas washed with water, dried over anhydrous magnesium sulfate andconcentrated in a vacuum. 50 ml of 1,4-dioxane was added to the residue,followed by the dropwise addition of 0.5 ml of concentrated sulfuricacid at room temperature. The obtained mixture was refluxed understirring for 30 minutes, cooled and poured onto ice-water. The obtainedmixture was extracted with ethyl acetate. The organic layer was washedwith water, dried over anhydrous magnesium sulfate and concentrated. 50ml of benzene was added to the residue to precipitate a crystal. Thiscrystal was recovered by filtration to give 1.0 g of the title compoundas a pale-yellow crystal.

m.p.: 202° to 203° C.

¹ H-NMR (400 MHz, CDCl₃) δ: 2.26 (d, J=7.2 Hz, 3H), 3.94 (s, 3H), 4.77(s, 2H), 6.28 (br s, 1H), 6.43 (q, J=7.2 Hz, 1H), 7.11 (s, 1H),7.11˜7.27 (m, 7H), 7.61 (br d, J=8.4 Hz, 1H).

MS m/z (Pos, FAB): 348 (M⁺).

EXAMPLE 2 ##STR47##

A part of a solution of 18.38 g of 1-bromopropane in 30 ml oftetrahydrofuran was added to a mixture comprising 3.63 g of magnesium,40 ml of tetrahydrofuran and a catalytic amount of iodine. The obtainedmixture was heated to initiate a reaction. The rest of the solution wasdropped into the resulting mixture in 10 minutes and the obtainedmixture was stirred at 80° C. for 30 minutes. Separately, 9.47 g of thecarboxylic acid prepared in the Referential Example 29 was dissolved in100 ml of tetrahydrofuran and the obtained solution was cooled with ice.The Grignard reagent prepared above was added to the solution in 10minutes, followed by the addition of a saturated aqueous solution ofammonium chloride. The obtained mixture was extracted with ethylacetate. The organic layer was dried over anhydrous magnesium sulfateand filtered. The filtrate was distilled to remove the solvent. Theresidue was dissolved in 100 ml of 1,4-dioxane, followed by the additionof 1.5 ml of concentrated sulfuric acid. The obtained mixture wasstirred on an oil bath at 120° C. for 18 minutes and poured ontoice-water. The obtained mixture was extracted with ethyl acetate. Theorganic layer was washed with a saturated aqueous solution of sodiumchloride twice, dried over anhydrous magnesium sulfate and filtered. Thefiltrate was distilled to remove the solvent. The residue was subjectedto silica gel column chromatography (developer: 20% ethylacetate/hexane). Diisopropyl ether was added to the obtained fraction toprecipitate a crystal. This crystal was recovered by filtration anddissolved in 320 ml of ethanol, followed by the addition of 500 mg ofNorit SX-3. The obtained mixture was stirred and filtered. The filtratewas concentrated and the precipitated crystal was recovered byfiltration. 2.21 g of the title compound was obtained.

m.p.: 194° to 196° C.

¹ H-NMR (400 MHz, CDCl₃) δ: 1.16 (t, J=7.5 Hz, 3H), 2.75 (quint, J=7.5Hz, 2H), 3.95 (s, 3H), 4.77 (br s, 2H), 6.28 (br s, 1H), 6.31 (t, J=7.5Hz, 1H), 7.11 (s, 1H), 7.1˜7.3 (m, 7H), 7.62 (dd, J=8.4 Hz, 0.9 Hz, 1H).

MS m/z (Pos, FAB): 362 (M⁺).

EXAMPLE 3 ##STR48##

A part of a solution of 25.39 g of 1-bromobutane in 40 ml oftetrahydrofuran was added to a mixture comprising 4.5 g of magnesium, 40ml of tetrahydrofuran and a catalytic amount of iodine. The obtainedmixture was heated to initiate a reaction. The rest of the solution wasdropped into the resulting mixture in 10 minutes and the obtainedmixture was stirred at 80° C. for one hour. Separately, 11.75 g of thecarboxylic acid prepared in the Referential Example 29 was dissolved in100 ml of tetrahydrofuran and the obtained solution was cooled with ice.The Grignard reagent prepared above was added to the solution in 10minutes, followed by the addition of ice-water and an aqueous solutionof ammonium chloride. The obtained mixture was extracted with ethylacetate under salting out and the organic layer was dried over anhydrousmagnesium sulfate.

The resulting mixture was filtered and the filtrate was distilled in avacuum to remove the solvent. The residue was dissolved in 120 ml of1,4-dioxane, followed by the addition of 1.8 ml of concentrated sulfuricacid. The obtained mixture was stirred on an oil bath at 120° C. for 20minutes and poured onto ice-water. The obtained mixture was extractedwith ethyl acetate. The organic layer was washed with a saturatedaqueous solution of sodium chloride twice, dried over anhydrousmagnesium sulfate and filtered. The filtrate was distilled to remove thesolvent. The residue was subjected to silica gel column chromatography(developer: 10 to 13% ethyl acetate/hexane). The obtained fraction wasrecrystallized from ethyl acetate/hexane. The obtained crystal wasdissolved in 150 ml of ethanol, followed by the addition of 400 mg ofNorit SX-3. The obtained mixture was stirred and filtered. The filtratewas concentrated to precipitate a crystal. This crystal was recovered byfiltration to give 1.91 g of the title compound.

m.p.: 170° to 172° C.

¹ H-NMR (400 MHz, CDCl₃)δ: 1.00 (t, J=7.3 Hz, 3H), 1.57 (sixtet, J=7.3Hz, 2H), 2.64 (q, J=7.3 Hz, 2H), 3.95 (s, 3H), 4.77 (s, 2H), 6.28 (br s,1H), 6.32 (t, J=7.3 Hz, 1H), 7.11 (s, 1H), 7.1˜7.28 (m, 7H), 7.62 (dd,J=8.5 Hz, 1.2 Hz, 1H).

MS m/z (Pos, FAB): 376 (M⁺).

EXAMPLE 4 ##STR49##

66.6 g of the carboxylic acid prepared in the Referential Example 29 wasdissolved in 200 ml of tetrahydrofuran to give a solution. 300 ml of a3M solution of isobutylmagnesium bromide in tetrahydrofuran was added tothe solution under cooling with ice. The obtained mixture was stirredfor 30 minutes and added to a saturated aqueous solution of ammoniumchloride. The obtained mixture was extracted with ethyl acetate. Theorganic layer was washed with a saturated aqueous solution of sodiumchloride, dried over anhydrous magnesium sulfate and distilled in avacuum to remove the solvent. The residue was dissolved in 500 ml of1,4-dioxane, followed by the addition of 5 ml of concentrated sulfuricacid. The obtained mixture was heated under reflux for 15 minutes andcooled to room temperature, followed by the addition of ethyl acetate.The obtained mixture was washed with water twice and with a saturatedaqueous solution of sodium chloride thrice. The organic layer was driedover anhydrous magnesium sulfate and distilled in a vacuum to remove thesolvent. The residue was purified by silica gel column chromatography(developer: 20% ethyl acetate/hexane) to give 9 g of the title compoundas a pale-yellow crystal.

m.p.: 190° to 192° C.

¹ H-NMR (400 MHz, CDCl₃)δ: 1.14 (d, J=6.6 Hz, 6H), 3.43˜3.60 (m, 1H),3.96 (s, 3H), 4.77 (br s, 2H), 6.10 (d, J=10.1 Hz, 1H), 6.24 (br s, 1H),7.10 (s, 1H), 7.10˜7.28 (m, 7H), 7.62 (br d, J=8.6 Hz, 1H).

MS m/z (Pos, FAB): 376 (M⁺).

EXAMPLE 5 ##STR50##

A part of a solution of 6.94 g of (bromomethyl)cyclopropane in 20 ml oftetrahydrofuran was added to a mixture comprising 1.25 g of magnesium,20 ml of tetrahydrofuran and a catalytic amount of iodine. The obtainedmixture was heated to initiate a reaction. The rest of the solution wasdropped into the resulting mixture in 5 minutes. The obtained mixturewas stirred at 80° C. for 30 minutes. Separately, 2.79 g of thecarboxylic acid prepared in the Referential Example 29 was dissolved in80 ml of tetrahydrofuran and the obtained solution was cooled with ice.The Grignard reagent prepared above was added to the solution, followedby the addition of a saturated aqueous solution of ammonium chloride.The obtained mixture was extracted with ethyl acetate. The organic layerwas dried over anhydrous magnesium sulfate and filtered. The filtratewas distilled to remove the solvent. The residue was dissolved in 30 mlof 1,4-dioxane, followed by the addition of 0.9 ml of concentratedsulfuric acid. The obtained mixture was stirred on an oil bath at 120°C. for one hour and poured onto ice-water. The obtained mixture wasextracted with ethyl acetate. The organic layer was washed with asaturated aqueous solution of sodium chloride twice, dried overanhydrous magnesium sulfate and filtered. The filtrate was distilled toremove the solvent. The residue was subjected to silica gel columnchromatography (developer: 20% ethyl acetate/hexane). Diisopropyl etherwas added to the obtained fraction. The obtained mixture was filtered toremove insolubles. The filtrate was distilled to remove the solvent. Theresidue was dissolved in diethylether, followed by the addition ofhexane. The obtained mixture was cooled with ice to precipitate acrystal. This crystal was recovered by filtration and dissolved in 17 mlof ethanol, followed by the addition of 370 mg of Norit SX-3. Theobtained mixture was stirred and filtered. The filtrate was distilled toremove the solvent. The residue was recrystallized from diethylether/hexane to give 220 mg of the title compound.

m.p.: 156° to 158° C.

¹ H-NMR (400 MHz, CDCl₃)δ: 3.51 (br t, J=7.6 Hz, 2H), 3.95 (s, 3H), 5.10(br d, J=10.0 Hz, 1H), 5.17 (br d, J=17.2 Hz, 1H), 5.88˜6.00 (m, 1H),6.30 (br s, 1H), 6.34 (t, J=7.6 Hz, 1H), 7.12 (s, 1H), 7.1˜7.3 (m, 7H),7.61 (br d, J=8.6 Hz, 1H).

MS m/z (Pos, FAB): 374 (M⁺).

EXAMPLE 6 ##STR51##

A part of a solution of 5 g of 5-bromo-2-methyl-2-pentene in 10 ml oftetrahydrofuran was added to a mixture comprising 750 mg of magnesium,10 ml of tetrahydrofuran and a catalytic amount of iodine. The obtainedmixture was heated to initiate a reaction. The rest of the solution wasdropped into the resulting mixture in 10 minutes. The obtained mixturewas stirred at 80° C. for 30 minutes. Separately, 2.33 g of thecarboxylic acid prepared in the Referential Example 29 was dissolved in60 ml of tetrahydrofuran and the obtained solution was cooled with ice.The Grignard reagent prepared above was added to the solution in 7minutes, followed by the addition of a saturated aqueous solution ofammonium chloride. The obtained mixture was extracted with ethylacetate. The organic layer was dried over anhydrous magnesium sulfateand filtered. The filtrate was distilled in a vacuum to remove thesolvent. The residue was dissolved in 25 ml of 1,4-dioxane, followed bythe addition of 0.45 ml of concentrated sulfuric acid. The obtainedmixture was stirred on an oil bath at 120° C. for 30 minutes and pouredonto ice-water. The obtained mixture was extracted with ethyl acetate.The organic layer was washed with a saturated aqueous solution of sodiumchloride twice, dried over anhydrous magnesium sulfate and filtered. Thefiltrate was distilled to remove the solvent. The residue was subjectedto silica gel column chromatography (developer: 10% ethylacetate/hexane). Diisopropyl ether was added to the obtained fraction toprecipitate a crystal. This crystal was recovered by filtration anddissolved in 25 ml of ethanol, followed by the addition of 60 mg ofNorit SX-3. The obtained mixture was stirred and filtered. The filtratewas distilled to remove the solvent. The residue was recrystallized fromdiethylether/hexane to give 90 mg of the title compound.

m.p.: 154° to 156.5° C.

¹ H-NMR (400 MHz, CDCl₃)δ: 1.69 (br s, 3H), 1.73 (br s, 3H), 3.46 (br t,J=7.5 Hz, 2H), 3.96 (s, 3H), 4.77 (br s, 2H), 5.2˜5.3 (m, 1H), 6.26 (t,J=7.5 Hz, 1H), 6.2˜6.35 (m, 1H), 7.12 (s, 1H), 7.1˜7.3 (m, 7H), 7.62 (brd, J=8.6 Hz, 1H).

MS m/z (Pos, FAB): 402 (M⁺).

EXAMPLES 7 TO 39

The carboxylic acids prepared in the Referential Examples 30 to 41 wereeach reacted with a suitable Grignard reagent, and then obtainedreaction mixtures were each treated in a similar manner to that of theExample 1 to give compounds listed in Table 2 as Examples 7 to 39.

                                      TABLE 2                                     __________________________________________________________________________    Ex. Objective compound                                                        No. structural formula and name                                                                            form  .sup.1 H-NMR (400 MHz) δ, MS                                            m/z                  m.p.                  __________________________________________________________________________                                                            (°C.)           7                                                                                 ##STR52##               light- brown crystal                                                                0.94 (t, J=7.5Hz, 3H), 1.41(sixtet,                                           J=7.5Hz, 2H), 1.52(quint, J=7.5Hz,                                            2H), 2.74(t, J=7.5Hz, 2H), 3.94(s,                                            3H), 4.78 (s, 2H), 6.32(t, J=7.5Hz,                                           1H), 6.10˜ 6.42(brs, 1H),                                               7.10˜7.30(m, 8H), 7.62 (dd,                                             J=7.5Hz, 1.3Hz, 1H) (CDCl.sub.3) (Pos,                                        FAB): 390 (M.sup.+)  173                    8                                                                                 ##STR53##               pale- yellow crystal                                                                0.91(t, J=7.0Hz, 3H),                                                         1.27˜1.45(m, 4H),                                                       1.46˜1.60(m, 2H), 2.74(q,                                               J=7.0Hz, 2H), 3.95(s, 3H), 4.77(s,                                            2H), 6.33(t, J=7.0Hz, 1H), 7.11(s,                                            1H), 7.08˜ 7.32(m, 7H), 7.62(d,                                         J=8.0Hz, 1H) (CDCl.sub.3) (Pos, FAB):                                         404 (M.sup.+)        129˜130          9                                                                                 ##STR54##               light- brown crystal                                                                2.95(q, J=7.4Hz, 2H), 3.42(s, 3H),                                            3.60 (t, J=7.4Hz, 2H), 3.94(s, 3H),                                           4.78(s, 2H), 6.28(brs, 1H), 6.32(t,                                           J=7.4Hz, 1H), 7.10˜7.28(m, 8H),                                         7.60(brd, J=8.3Hz, 1H) (CDCl.sub.3)                                                                138˜141         10                                                                                 ##STR55##               light- brown crystal                                                                3.96(s, 3H), 4.80(s, 2H), 6.36(brs,                                           1H), 7.04(s, 1H), 7.06˜7.59(m,                                          12H), 7.88(brd, J=8.3Hz,                                                      1H) (CDCl.sub.3)     135˜138         11                                                                                 ##STR56##               pale- yellow crystal                                                                3.94(s, 3H), 4.11(d, J=7.7Hz, 2H),                                            4.76 (brs, 2H), 6.29(brs, 1H),                                                6.48(brt, J=7.7Hz, 1H),                                                       7.10˜7.35(m, 13H), 7.64 (brd,                                           J=8.8Hz, 1H) (CDCl.sub.3) (Pos, FAB):                                         424 (M.sup.+)        179˜182         12                                                                                 ##STR57##               reddish purple crystal                                                              1.00˜2.00(m, 10H),                                                      3.10˜3.30(m, 1H), 3.96(s, 3H),                                          4.78(brs, 2H), 6.12(d, J=10.1Hz, 1H),                                         6.29(brs, 1H), 7.10(s, 1H),                                                   7.10˜7.30(m, 7H), 7.63(brd,                                             J=8.5Hz, 1H) (CDCl.sub.3) (Pos, FAB):                                         416 (M.sup.+)        186.5˜188.5                                                             1                     13                                                                                 ##STR58##               pale- yellow crystal                                                                1.29(s, 9H), 3.95(s, 3H), 4.76(s, 2H),                                        .85(s, 1H), 6.28(brs, 1H),                                                    7.05˜7.30 (m, 8H), 7.89(d,                                              J=8.4Hz, 1H) (CDCl.sub.3) (Pos, FAB):                                         390 (M.sup.+)        163˜164         14                                                                                 ##STR59##               light- brown crystal                                                                3.92(s, 3H), 4.75(s, 2H), 5.96(s, 1H),                                        .31(brs, 1H), 6.78(s, 1H),                                                    7.06˜7.18 (m, 8H), 7.52(brd,                                            J=8.3Hz, 1H) (CDCl.sub.3)                                                                          191˜194         15                                                                                 ##STR60##               light- brown crystal                                                                1.56(s, 3H), 2.32(s, 3H), 3.92(s, 3H),                                        .76(s, 2H), 6.28(brs, 1H), 7.04(s,                                            1H), 7.10˜7.30(m, 7H), 7.56(brd,                                        =8.3Hz, 1H) (CDCl.sub.3)                                                                           168.5˜169.0                                                             0                     16                                                                                 ##STR61##               purple crystal                                                                      0.84(t, J=7.5Hz, 3H), 1.22(t, J=7.5Hz,                                        H), 1.72˜1.94(m, 2H),                                                   2.50˜2.62(m, 1H),                                                       2.77˜2.90(m, 1H), 3.94(s, 3H),                                          4.78(s, 2H), 6.28(brs, 1H), 7.04(s,                                           1H), 7.06˜7.36(m, 7H), 7.58(brd,                                        J=8.5Hz, 1H) (CDCl.sub.3)                                                                          188˜189         17                                                                                 ##STR62##               pale- purple crystal                                                                2.26(d, J=7.2Hz, 3H), 3.94(s, 3H),                                            4.70 (s, 2H), 6.24(brs, 1H), 6.46(q,                                          J=7.2Hz, 1H), 7.04˜7.28(m, 7H),                                         7.60(brd, J=8.5Hz, 1H) (CDCl.sub.3)                                                                176.5˜177       18                                                                                 ##STR63##               pale-red crystal                                                                    1.56(s, 3H), 2.32(s, 3H), 3.92(s, 3H),                                        .70(s, 2H), 6.25(brs, 1H), 7.04(s,                                            1H), 7.06˜7.28(m, 6H), 7.56(brd,                                        J=8.3Hz, 1H) (CDCl.sub.3)                                                                          176.5                 19                                                                                 ##STR64##               pale-red crystal                                                                    1.58(s, 3H), 2.35(s, 3H), 3.76(s, 3H),                                        .94(s, 3H), 4.71(s, 2H), 6.30(s, 1H),                                         6.80(d, J=7.0Hz, 2H),                                                         7.02˜7.28(m, 5H), 7.54(brd,                                             J=8.4Hz, 1H) (CDCl.sub.3)                                                                          143.0                 20                                                                                 ##STR65##               pale- purple crystal                                                                1.56(s, 3H), 2.30(s, 3H), 2.34(s, 3H),                                        .92(s, 3H), 4.74(s, 2H), 6.28(s, 1H),                                         7.00˜7.14(m, 5H), 7.20(brt,                                             J=8.3Hz, 1H), 7.26(s, 1H), 7.54(brd,                                          J=8.3Hz, 1H) (CDCl.sub.3)                                                                          162.5˜163.0     21                                                                                 ##STR66##               gray crystal                                                                        1.42(t, J=7.0Hz, 3H), 2.28(d, J=7.3Hz,                                        H), 4.18(q, J=7.0Hz, 2H), 4.78(s, 2H),                                        6.36(s, 1H), 6.42(q, J=7.3Hz, 1H),                                            7.00˜ 7.32(m, 8H), 7.60(d,                                              J=8.3Hz, 1H)         166˜168         22                                                                                 ##STR67##               bluish- purple crystal                                                              1.44(t, J=7.0Hz, 3H), 1.60(s, 3H),                                            2.36 (s, 3H), 4.18(q, J=7.0Hz, 2H),                                           4.80(s, 2H), 6.36(brs, 1H),                                                   6.98˜7.36(m, 8H), 7.56(brd,                                             J=8.5Hz, 1H) (CDCl.sub.3)                                                                          173˜175         23                                                                                 ##STR68##               gray crystal                                                                        1.04(t, J=7.0Hz, 3H),                                                         1.76˜1.90(m, 2H), 2.26(d,                                               J=7.2Hz, 3H), 4.06(t, J=7.0Hz, 2H),                                           4.78(s, 2H), 6.34(s, 1H), 6.42(q,                                             J=7.2Hz, 1H), 7.00˜7.30(m, 8H),                                         7.60 (brd, J=8.4Hz, 1H) (CDCl.sub.3)                                                               195˜197         24                                                                                 ##STR69##               bluish- purple crystal                                                              1.04(t, J=7.0Hz, 3H), 1.56(s, 3H),                                            1.78˜ 1.88(m, 2H), 2.33(s, 3H),                                         4.05(t, J=7.0Hz, 2H), 4.78(s, 2H),                                            6.35(brs, 1H), 7.03(s, 1H),                                                   7.06˜7.30(m, 7H), 7.56 (brd,                                            J=8.4Hz, 1H) (CDCl.sub.3)                                                                          173˜175         25                                                                                 ##STR70##               pale- yellow crystal                                                                1.36(d, J=6.8Hz, 6H), 2.26(d, J=7.3Hz,                                        H), 4.56˜4.64(m, 1H), 4.78(s,                                           2H), 6.42(s, 1H), 6.43(q, J=7.3Hz,                                            1H), 7.02˜ 7.28(m, 8H),                                                 7.60(brd, J=8.3Hz, 1H)                                                                             181˜183         26                                                                                 ##STR71##               brown crystal                                                                       1.34(d, J=6.8Hz, 6H), 1.56(s, 3H),                                            2.30 (s, 3H), 4.52˜4.62(m, 1H),                                         4.78(s, 2H),  6.40(brs, 1H), 7.02(s,                                          1H), 7.06˜7.30 (m, 7H),                                                 7.56(brd, J=8.3Hz, 1H) (CDCl.sub.3)                                                                212˜214         27                                                                                 ##STR72##               bluish- purple crystal                                                              0.98(t, J=7.3Hz, 3H),                                                         1.42˜1.56(m, 2H), 1.72˜1.84                                       (m, 2H), 2.26(d, J=7.2Hz, 3H), 4.11(t,                                        J=7.3Hz, 2H), 4.78(s, 2H), 6.34 (s,                                           1H), 6.42(q, J=7.2Hz, 1H),                                                    7.02˜7.30 (m, 8H), 7.60(brd,                                            J=8.4Hz, 1H) (CDCl.sub.3)                                                                          196˜198         28                                                                                 ##STR73##               bluish- purple crystal                                                              0.98(t, J=7.2Hz, 3H)                                                          1.42˜1.58(m, 2H), 1.58(s, 3H),                                          1.72˜1.84(m, 2H), 2.34(s, 3H),                                          4.10(t, J=7.2Hz, 2H), 4.78(s, 2H),                                            6.34(s, 1H), 7.00˜7.32(m, 8H),                                          7.56 (brd, J=8.5Hz, 1H) (CDCl.sub.3)                                                               182˜184         29                                                                                 ##STR74##               gray crystal                                                                        1.60˜1.98(m, 8H), 2.28(d,                                               J=7.2Hz, 3H), 4.76(s, 2H),                                                    4.86˜4.94(m, 1H), 6.32(s, 1H),                                          6.45(q, J=7.2Hz, 1H),                                                         7.04˜7.36(m, 8H), 7.60(brd,                                             J=8.4Hz, 1H) (CDCl.sub.3)                                                                          200˜201         30                                                                                 ##STR75##               bluish- purple crystal                                                              1.56(s, 3H), 1.60˜1.94(m, 8H),                                          2.32(s, 3H), 4.76(s, 2H),                                                     4.84˜4.90(m, 1H), 6.32(s, 1H),                                          7.04(s, 1H), 7.08˜7.36(m, 7H),                                          7.54(d, J=8.0Hz, 1H) (CDCl.sub.3)                                                                  211˜213         31                                                                                 ##STR76##               light- blown crystal                                                                1.15(t, J=7.5Hz, 3H),                                                         1.60˜1.96(m, 8H), 2.75(quint,                                           J=7.5Hz, 2H), 4.76(s,                                                         2H), 4.86˜4.92(m, 1H), 6.30(t,                                          J=7.5Hz, 1H), 6.32(s, 1H),                                                    7.08˜7.30(m, 8H), 7.60 (dd,                                             J=8.5Hz, 0.9Hz, 1H) (CDCl.sub.3)                                                                   191˜193         32                                                                                 ##STR77##               colorless crystal                                                                   2.26(d, J=7.0Hz, 3H), 2.28(s, 3H),                                            4.73 (s, 2H), 6.36(q, J=7.0Hz, 1H),                                           7.12(s, 1H), 7.05˜7.30(m, 6H),                                          7.32(t, J=8.0Hz, 1H), 7.68(d, J=8.0Hz,                                        1H) (CDCl.sub.3) (Pos, FAB): 332                                              (M.sup.+)            173˜175         33                                                                                 ##STR78##               pale- yellow crystal                                                                1.57(s, 3H), 2.29(s, 3H), 2.33(s, 3H),                                        .73(d, J=20Hz, 1H), 4.77(d, J=20Hz,                                           1H), 7.07(s, 1H), 7.12˜7.35(m,                                          7H), 7.65(d, J=8.0Hz, 1H) (CDCl.sub.3)                                        Pos, FAB): 346 (M.sup.+)                                                                           202˜204         34                                                                                 ##STR79##               colorless crystal                                                                   1.24(t, J=7.0Hz, 3H), 2.26(d, J=7.0Hz,                                        H), 2.66(q, J=7.0Hz, 2H), 4.76(s, 2H),                                        .34(q, J=7.0Hz, 1H),                                                          7.05˜7.37(m, 8H), 7.70(d,                                               J=8.0Hz, 1H) (CDCl.sub.3) (Pos, FAB):                                         346 (M.sup.+)        193˜195         35                                                                                 ##STR80##               colorless crystal                                                                   1.25(t, J=7.0Hz, 3H), 1.58(s, 3H),                                            2.35 (s, 3H), 2.66(q, J=7.0Hz, 2H),                                           4.73(d, J=20Hz, 1H), 4.77(d, J=20Hz,                                          1H), 7.09(s, 1H), 7.12˜7.36(m,                                          7H), 7.65(d, J=8.0Hz, 1H) (CDCl.sub.3)                                        Pos, FAB): 360 (M.sup.+)                                                                           166˜168         36                                                                                 ##STR81##                colorless crystal                                                                  0.97(t, J=7.0Hz, 3H),                                                         1.55˜1.72(m, 2H), 2.27(d,                                               J=7.0Hz, 3H), 2.60(t, J=7.0Hz, 2H),                                           4.75(s, 2H), 6.37(q, J=7.0Hz, 1H),                                            7.12(s, 1H), 7.10˜7.32(m, 6H),                                          7.33(t, J=8.0Hz, 1H), 7.68(d, J=8.0Hz,                                        1H) (CDCl.sub.3) (Pos, FAB): 360                                              (M.sup.+)            164˜167         37                                                                                 ##STR82##               colorless crystal                                                                   0.95(t, J=7.0Hz, 3H), 1.58(s, 3H),                                            1.45˜ 1.67(m, 2H), 2.34(s, 3H),                                         2.52˜2.70(m, 2H), 4.70(d,                                               J=20Hz, 1H), 4.78(d, J=20Hz, 1H,                                              5.12(brs, 1H), 7.04(s, 1H),                                                   7.10˜ 7.34(m, 7H), 7.62(d,                                              J=8.0Hz, 1H) (CDCl.sub.3) (Pos, FAB):                                         3.74 (M.sup.+)       163˜165         38                                                                                 ##STR83##               colorless crystal                                                                   0.91(t, J=7.0Hz, 3H),                                                         1.30˜1.45(m, 2H), 1.51˜1.70                                       (m, 2H), 2.16(d, J= 7.0Hz, 3H),                                               2.62(t, J=7.0Hz, 2H), 4.75(s, 2H),                                            6.36 (q, J=7.0Hz, 1H), 7.12(s, 1H),                                           7.10˜7.32 (m, 6H), 7.33(t,                                              J=8.0Hz, 1H), 7.69(d, J=8.0Hz, 1H)                                            (CDCl.sub.3) (Pos, FAB): 374                                                                       174˜176         39                                                                                 ##STR84##               pale- yellow crystal                                                                0.92(t, J=7.0Hz, 3H),                                                         1.28˜1.44(m, 2H), 1.45˜1.72                                       (m, 2H), 1.59(s, 3H), 2.36(s, 3H),                                            2.62(t, J=7.0Hz, 2H), 4.71(d, J=16Hz,                                         1H), 4.78(d, J=16Hz, 1H), 5.09(s, 1H),                                        7.05(s, 1H), 7.08˜7.47(m, 7H),                                          7.62(d, J=8.0Hz, 1H) (CDCl.sub.3)                                                                  194˜196         __________________________________________________________________________

EXAMPLE 40 ##STR85##

2.78 g of ethyltriphenylphosphonium bromide was suspended in 20 ml oftetrahydrofuran to give a suspension. 3.0 ml of a 2.5M solution ofn-butyllithium in hexane was dropped into the suspension in a stream ofnitrogen at -70° C. in 5 minutes. The temperature of the resultingmixture was raised to 0° C. The resulting mixture was stirred for 30minutes. A solution of 1.98 g of the ketoester prepared in theReferential Example 12 in 10 ml of tetrahydrofuran was added to themixture in 5 minutes. The obtained mixture was stirred at 0° C. for 30minutes and at room temperature for 2 hours, followed by the addition of20 ml of an aqueous solution of ammonium chloride. The obtained mixturewas stirred for 2 hours and extracted with ether. The organic layer waswashed with water, dried over anhydrous magnesium sulfate and purifiedby silica gel column chromatography (developer: 5% ethyl acetate/hexane)to give 1.2 g of the title compound as a colorless oil. ##STR86##

1.2 g of the ester prepared in the step (a) was dissolved in 50 ml ofethanol, followed by the addition of 10 ml of water and 3 g of sodiumhydroxide. The obtained mixture was stirred at 80° C. for 30 minutes,cooled and poured onto ice-water. The obtained mixture was made weaklyacidic with dilute hydrochloric acid and extracted with ethyl acetate.The organic layer was washed with water, dried over anhydrous magnesiumsulfate and concentrated. 20 ml of acetone and 20 ml of 6N hydrochloricacid were added to the residue. The obtained mixture was stirred at roomtemperature for 2 hours, followed by the addition of 100 ml of asaturated aqueous solution of sodium chloride. The obtained mixture wasextracted with ethyl acetate. The organic layer was washed with water,dried over anhydrous magnesium sulfate and concentrated. The residue wasrecrystallized from diisopropylether to give 350 mg of the titlecompound as a colorless crystal.

m.p.: 190° to 192° C.

¹ H-NMR (400 MHz, CDCl₃) δ: 1.61 (d, J=7.2 Hz, 3H), 3.92 (s, 3H), 4.87(s, 2H), 6.30 (br s, 1H), 7.02 (s, 1H), 7.08˜7.26 (m, 7H), 7.42˜7.56 (m,2H).

MS m/z (Pos, FAB): 348 (M⁺).

EXAMPLE 41 ##STR87##

1.47 g of the ketoester prepared in the Referential Example 24 wasdissolved in 50 ml of 1,2-dimethoxyethane, followed by the addition of0.17 g of sodium hydride (55% suspension in oil) and 1.51 g ofmethyltriphenylphosphonium bromide. The obtained mixture was heatedunder reflux for 2 hours and cooled by allowing to stand, followed bythe addition of ethyl acetate. The obtained mixture was washed withwater and the organic layer was dried over anhydrous magnesium sulfateand concentrated in a vacuum. The residue was purified by silica gelcolumn chromatography (developer: 5% ethyl acetate/hexane) to give 700mg of the title compound as a colorless oil.

¹ H-NMR (400 MHz, CDCl₃) δ: 1.18 (t, J=7.3 Hz, 3H), 1.30 (br s, 3H),1.42 (br s, 3H), 3.50 (s, 3H), 3.92 (s, 3H), 4.08 (q, J=7.3 Hz, 2H),4.81 (br s, 2H), 5.08 (s, 2H), 5.20 (s, 1H), 5.67 (s, 1H), 7.04 (s, 1H),7.08˜7.36 (m, 7H), 7.84 (br d, J=8.3 Hz, 1H). ##STR88##

700 mg of the ethyl 3-butenoate prepared in the step (a) was suspendedin ethanol/water (30 ml/10 ml), followed by the addition of 200 mg ofpotassium hydroxide. The obtained mixture was heated under reflux for 6hours and cooled by allowing to stand, followed by the addition ofwater. The obtained mixture was acidified with dilute hydrochloric acidand extracted with ethyl acetate. The organic layer was washed withwater, dried over anhydrous magnesium sulfate and concentrated in avacuum. The obtained residue was used in the subsequent step withoutbeing purified. ##STR89##

The carboxylic acid prepared in the step (b) was dissolved in 5 ml ofacetone, followed by the addition of 2 ml of 6N hydrochloric acid. Theobtained mixture was stirred at room temperature for one hour, followedby the addition of ethyl acetate. The organic layer was washed withwater, dried over anhydrous magnesium sulfate and distilled in a vacuumto remove the solvent. The obtained solid was washed withdiisopropylether to give 300 mg of the title compound as a colorlesscrystal.

m.p.: 162.5° C.

¹ H-NMR (400 MHz, CDCl₃) δ: 1.24 (br s, 3H), 1.46 (br s, 3H), 3.78 (s,3H), 4.78 (s, 2H), 5.24 (s, 1H), 5.72 (s, 1H), 6.18 (s, 1H), 7.06 (s,1H), 7.08˜7.30 (m, 7H), 7.82 (br d, J=8.2 Hz, 1H).

EXAMPLE 42 ##STR90##

1.72 g of diethyl cyanomethylphosphonate was dissolved in 50 ml ofN,N-dimethylformamide, followed by the addition of 0.44 g of sodiumhydride (55% suspension in oil). A solution of 3.56 g of the ketoesterprepared in the Referential Example 12 in 10 ml of N,N-dimethylformamidewas dropped into the mixture under cooling with ice. After thecompletion of the reaction, the reaction mixture was poured ontowater-ethyl acetate. The obtained mixture was washed with water twice.The organic layer was dried over anhydrous sodium sulfate and distilledin a vacuum to remove the solvent. The obtained residue was purified bysilica gel column chromatography (developer: 10% ethyl acetate/hexane)to give 3.59 g of the title compound as a reddish-brown oil. ##STR91##

0.79 g of the cyano derivative prepared in the step (a) was dissolved inmethanol/water (45 ml/5 ml), followed by the addition of 0.8 ml of 8Nsodium hydroxide. The obtained mixture was stirred at room temperature.After the completion of the reaction, the reaction mixture wasneutralized with 1N hydrochloric acid and extracted with ethyl acetateunder salting out. The organic layer was dried over anhydrous sodiumsulfate and distilled in a vacuum to remove the solvent.

¹ H-NMR (400 MHz, CDCl₃) δ: 3.48 (s, 3H), 3.9 (s, 3H), 4.8 (s, 2H), 5.12(s, 2H), 4.76 (s, 1H), 7.0˜7.34 (m, 10H). ##STR92##

0.80 g of the carboxylic acid prepared in the step (b) was dissolved in15 ml of acetone, followed by the addition of 0.5 ml of concentratedhydrochloric acid. The obtained mixture was stirred at room temperature.After the completion of the reaction, the reaction mixture was pouredinto water and the obtained mixture was extracted with ethyl acetate.The organic layer was dried over anhydrous sodium sulfate and distilledin a vacuum to remove the solvent. The obtained residue was purified bysilica gel column chromatography (developer: 0 to 10%methanol/dichloromethane) to give 0.35 g of the title compound as apale-yellow powder.

m.p.: 175° C. (dec.).

¹ H-NMR (400 MHz, DMSO-d₆) δ: 3.85 (s, 3H), 4.72 (s, 2H), 6.78 (s, 1H),7.0˜7.25 (m, 8H), 7.3 (s, 1H), 7.37 (s, 1H), 9.25 (s, 1H).

MS m/z (Pos, FAB): 359 (M⁺).

EXAMPLE 43 TO 52

The ketoesters prepared in the Referential Examples 12 to 21, 23 and 28were each reacted with a suitable Wittig reagent, and then the reactionmixtures were each treated in a similar manner to that of the Example 40to give compounds listed in Table 3 as Examples 43 to 52.

                                      TABLE 3                                     __________________________________________________________________________    Ex. Objective compound                                                        No. structural formula and name                                                                            form  .sup.1 H-NMR (400 MHz) δ, MS                                            m/z                  m.p.                  __________________________________________________________________________                                                            (°C.)          43                                                                                 ##STR93##               pale- yellow crystal                                                                0.95(t, J=7.5Hz, 3H), 1.94(quint,                                             J=7.5Hz, 2H), 3.92(s, 3H), 4.76(s,                                            2H), 6.30(brs, 1H), 7.00(s, 1H),                                              7.08˜7.18 (m, 7H), 7.38(t,                                              J=7.5Hz, 1H), 7.46(brd, J=8.4Hz, 1H)                                          (CDCl.sub.3)         187˜188         44                                                                                 ##STR94##               pale- yellow crystal                                                                0.82(t, J=7.3Hz, 3H), 1.40(sixtet,                                            J=7.3Hz, 2H), 1.90(q, J=7.3Hz, 2H),                                           3.92 (s, 3H), 4.77(s, 2H), 6.30(brs,                                          1H), 7.00 (s, 1H), 7.10˜7.28(m,                                         7H), 7.40(t, J=7.3Hz, 1H), 7.46(brd,                                          J=8.3Hz, 1H) (CDCl.sub.                                                                            168˜169         45                                                                                 ##STR95##               pale- yellow crystal                                                                0.78(t, J=7.7Hz, 3H), 1.22(sixtet,                                            J=7.7Hz, 2H), 1.37(quint, J=7.7Hz,                                            2H), 1.93(dt, J=7.5Hz, 7.7Hz, 2H),                                            3.92(s, 3H), 4.79(s, 2H), 6.31(brs,                                           1H), 7.01(s, 1H), 7.12˜7.27(m,                                          8H), 7.41(t, J=7.5Hz, 1H, 7.48(dd,                                            J=8.4Hz, 1.3Hz, 1H) (CDCl.sub.3) (Pos,                                        FAB): 390 (M.sup.+)  134                   46                                                                                 ##STR96##               colorless crystal                                                                   1.42˜2.18(m, 6H),                                                       2.92˜3.09(m, 2H), 3.92(s, 3H),                                          4.78(s, 2H), 6.26(brs, 1H), 7.04(s,                                           1H), 7.08˜7.28(m, 7H), 7.52                                             (brd, J=8.4Hz, 1H) (CDCl.sub.3)                                                                    192˜194         47                                                                                 ##STR97##               colorless crystal                                                                   3.84(s, 3H), 4.68(s, 2H), 5.83(s, 1H),                                        .44(s, 1H), 7.04˜7.28(m, 7H),                                           7.38 (brd, J=8.4Hz, 1H), 9.04(s, 1H),                                         12.66 (brs, 1H) (DMSO-d.sub.6)                                                                     above 200 (dec.)      48                                                                                 ##STR98##               yellow crystal                                                                      3.86(s, 3H), 3.94(s, 3H), 4.72(s, 2H),                                        .98(s, 1H), 6.28(brs, 1H),                                                    6.74˜6.84 (m, 3H), 6.90(brd,                                            J=8.2Hz, 1H), 7.05 (brd, J=8.2Hz, 1H),                                        7.10˜7.26(m, 3H), 7.54(brd,                                             J=8.3Hz, 1H) (CDCl.sub.3)                                                                          195˜198         49                                                                                 ##STR99##               pale- yellow crystal                                                                2.26(s, 3H), 4.75(s, 2H), 5.76(s, 1H),                                        .42(s, 1H), 7.00˜7.42(m, 9H),                                           8.77(s, 1H), 12.62(brs,                                                       1H) (DMSO-d.sub.6)   167˜169         50                                                                                 ##STR100##              yellow crystal                                                                      0.88 (t, J=7.2Hz, 3H),                                                        1.24˜1.37(m, 2H), 1.40˜1.54                                       (m, 2H), 2.66(t, J=7.2Hz, 2H), 4.76(s,                                        3H), 5.78(s, 1H), 6.42(s, 1H),                                                6.98˜7.40(m, 9H), 8.72(s, 1H),                                          12.62 (brs, 1H) (DMSO-d.sub.6)                                                                     167˜170         51                                                                                 ##STR101##              yellow crystal                                                                      0.90(t, J=7.3Hz, 3H),                                                         1.30˜1.44(m, 4H), 1.63˜1.76                                       (m, 2H), 3.28(t, J=7.3Hz, 2H), 3.98(s,                                        3H), 5.95(s, 1H), 6.40(brs, 1H),                                              6.76(s, 1H), 7.12(s, 1H),                                                     7.14˜7.26(m, 2H), 7.48(brd,                                             J=8.3Hz, 1H) (CDCl.sub.3)                                                                          158˜159         52                                                                                 ##STR102##              colorless crystal                                                                   2.48(t, J=7.0Hz, 2H), 2.82(t, J=7.0Hz,                                        H), 3.94(s, 3H), 4.78(s, 2H), 5.12(s,                                         1H), 5.42(s, 1H), 6.24(brs, 1H),                                              7.04(s, 1H), 7.10˜ 7.27(m, 7H),                                         7.76(brd, J=8.4Hz, 1H) (CDCl.sub.3)                                                                137˜138         __________________________________________________________________________

EXAMPLE 53 ##STR103##

26 g of the ester prepared in the Referential Example 22 was dissolvedin ethanol/water (300 ml/50 ml), followed by the addition of 6 g ofsodium hydroxide. The obtained mixture was stirred under heating for 30minutes, followed by the addition of 300 ml of 1N hydrochloric acid. Theobtained mixture was extracted with ethyl acetate. The organic layer waswashed with a saturated aqueous solution of sodium chloride, dried overanhydrous magnesium sulfate and distilled in a vacuum to remove thesolvent. The residue was dissolved in 250 ml of tetrahydrofuran to givea solution. 188 ml of a 2M solution of isopropylmagnesium chloride intetrahydrofuran was dropped into the solution under cooling with ice.After the completion of the dropping, the obtained mixture was stirredunder cooling with ice for one hour, followed by the addition of 300 mlof a saturated aqueous solution of ammonium chloride. The obtainedmixture was extracted with ethyl acetate. The organic layer was washedwith a saturated aqueous solution of sodium chloride, dried overanhydrous magnesium sulfate and distilled in a vacuum to remove thesolvent. The residue was dissolved in 300 ml of 1,4-dioxane, followed bythe addition of 5 ml of concentrated sulfuric acid. The obtained mixturewas stirred under heating for one hour and cooled to room temperature,followed by the addition of 300 ml of water. The obtained mixture wasextracted with ethyl acetate. The organic layer was washed with asaturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate and distilled in a vacuum to remove the solvent. Theresidue was purified by silica gel column chromatography (developer: 20%ethyl acetate/hexane) to give 5.6 g of the title compound as a yellowpowder.

¹ H-NMR (400 MHz, CDCl₃) δ: 1.58 (s, 3H), 2.32 (s, 3H), 3.71 (s, 3H),4.69 (s, 2H), 6.75 (d, J=8.0 Hz, 1H) 6.95˜7.28 (m, 7H), 7.25 (t, J=8.0Hz, 1H), 7.62 (d, J=8.0 Hz, 1H). ##STR104##

5.6 g of the carboxylic acid prepared in the step (a) was dissolved inmethanol/dichloromethane (50 ml/10 ml) to give a solution. 20 ml of a10% solution of trimethylsilyldiazomethane in dichloromethane wasdropped into the solution under cooling with ice. The obtained mixturewas stirred for 30 minutes and distilled in a vacuum to remove thesolvent. 5.1 g of the title compound was obtained as a pale-yellowpowder.

¹ H-NMR (400 MHz, CDCl₃) δ: 1.55 (s, 3H), 2.29 (s, 3H), 3.58 (s, 3H),3.72 (s, 3H), 4.71 (s, 2H), 6.95 (d, J=8.0 Hz, 1H), 7.05˜7.28 (m, 7H),7.36 (t, J=8.0 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H). ##STR105##

5.1 g of the methyl ester prepared in the step (b) was dissolved in 100ml of dichloromethane to give a solution. 2.3 ml of titaniumtetrachloride was added to the solution under cooling with ice, followedby the dropwise addition of 1.9 ml of dichloromethyl methyl ether. Theobtained mixture was stirred under cooling with ice for 30 minutes andpoured onto ice-water. The obtained mixture was extracted withdichloromethane. The organic layer was washed with a saturated aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate anddistilled in a vacuum to remove the solvent. The residue was purified bysilica gel column chromatography (developer: 10% ethyl acetate/hexane)to give 4.2 g of the title compound as a yellow oil.

¹ H-NMR (400 MHz, CDCl₃) δ: 1.54 (s, 3H), 2.33 (s, 3H), 3.57 (s, 3H),3.84 (s, 3H), 4.73 (s, 2H), 7.06˜7.33 (m, 6H), 7.49 (t, J=8.0 Hz, 1H),7.66 (s, 1H), 7.73 (d, J=8.0 Hz, 1H), 10.52 (s, 1H). ##STR106##

4.2 g of the formyl derivative prepared in the step (c) was dissolved in50 ml of dichloromethane to give a solution. 11 ml of a 1M solution ofboron tribromide in dichloromethane was added to the solution undercooling. The obtained mixture was stirred for 30 minutes and poured ontoice-water. The obtained mixture was extracted with dichloromethane. Theorganic layer was dried over anhydrous magnesium sulfate and distilledin a vacuum to remove the solvent. The residue was purified by silicagel column chromatography (developer: 6% ethyl acetate/hexane) to give3.75 g of the title compound as a yellow powder.

¹ H-NMR (400 MHz, CDCl₃) δ: 1.59 (s, 3H), 2.32 (s, 3H), 3.60 (s, 3H),4.84 (s, 2H), 7.20 (d, J=8.0 Hz, 2H), 7.12˜7.32 (m, 5H), 7.53 (t, J=8.0Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 9.87 (s, 1H), 13.36 (s, 1H). ##STR107##

3.75 g of the phenol prepared in the step (d) was dissolved indichloromethane, followed by the addition of 5.2 ml ofdiisopropylethylamine. 1.5 ml of chloromethyl methyl ether was droppedinto the obtained mixture. The obtained mixture was stirred at roomtemperature for one hour and washed with 1% aqueous hydrochloric acid.The organic layer was dried over anhydrous magnesium sulfate anddistilled in a vacuum to remove the solvent. 4.19 g of the titlecompound was obtained as a crude product. ##STR108##

4.19 g of the methoxymethyl ether prepared in the step (e) was dissolvedin 40 ml of tetrahydrofuran. The obtained solution was cooled to -70°C., followed by the dropwise addition of 8 ml of a 1.5M solution ofmethyllithium in ether. The obtained mixture was stirred at -70° C. for20 minutes, followed by the addition of a saturated aqueous solution ofammonium chloride. The obtained mixture was extracted with ethylacetate. The organic layer was dried over anhydrous magnesium sulfateand distilled in a vacuum to remove the solvent. The residue waspurified by silica gel column chromatography (developer: 20% ethylacetate/hexane) to give 3.35 g of the title compound as a pale-yellowoil.

¹ H-NMR (400 MHz, CDCl₃) δ: 1.45˜1.62 (m, 3H), 1.54 (s, 3H), 2.31 (s,3H), 3.54 (s, 3H), 3.58 (s, 3H), 4.64 (d, J=16 Hz, 1H), 4.73 (d, J=16Hz, 1H), 4.70˜4.87 (m, 2H), 5.38˜5.52 (m, 1H), 7.07˜7.45 (m, 8H), 7.67(d, J=8.0 Hz, 1H). ##STR109##

3.35 g of the alcohol prepared in the step (f) was dissolved in 200 mlof dichloromethane, followed by the addition of 25 g of manganesedioxide. The obtained mixture was heated under reflux for 2 hours,cooled to room temperature and filtered through Celite. THe filtrate wasdistilled in a vacuum to remove the solvent. 3.33 g of the titlecompound was obtained as a yellow oil in a crude state.

¹ H-NMR (400 MHz, CDCl₃) δ: 1.54 (s, 3H), 2.32 (s, 3H), 2.64 (s, 3H),3.32 (s, 3H), 3.58 (s, 3H), 4.73 (d, J=16 Hz, 1H), 4.79 (d, J=16 Hz,1H), 4.80 (d, J=12 Hz, 1H), 4.83 (d, J=12 Hz, 1H), 7.10˜7.33 (m, 6H),7.37 (s, 1H), 7.41 (t, J=8.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H). ##STR110##

3 g of the acetyl derivative prepared in the step (g) was dissovled in40 ml of dimethoxyethane, followed by the addition of 3 g ofmethyltriphenylphosphonium bromide and 0.4 g of sodium hydride (55%suspension in oil). The obtained mixture was stirred under heating forone hour, cooled to room temperature and poured onto ice-water. Theobtained mixture was extracted with ethyl acetate. The organic layer wasdried over anhydrous magnesium sulfate and distilled in a vacuum toremove the solvent. The residue was purified by silica gel columnchromatography (developer: 10% ethyl acetate/hexane) to give 1.65 g ofthe title compound as a yellow oil.

¹ H-NMR (400 MHz, CDCl₃) δ: 1.54 (s, 3H), 2.19 (s, 3H), 2.28 (s, 3H),3.43 (s, 3H), 3.59 (s, 3H), 4.81 (s, 2H), 4.79 (s, 2H), 5.17 (d, J=1.8Hz, 1H), 5.25 (d, J=1.8 Hz, 1H), 7.10˜7.32 (m, 8H), 7.63 (d, J=8.0 Hz,1H). ##STR111##

1.1 g of the isopropenyl derivative prepared in the step (h) wasdissolved in methanol/tetrahydrofuran (30 ml/10 ml), followed by theaddition of 0.5 g of 10% Pd-C (containing 50% of water). The obtainedmixture was stirred at room temperature in an atmosphere of hydrogen for5 hours and filtered through Celite. The filtrate was distilled in avacuum to give 1.1 g of the title compound in a crude state as a yellowoil.

¹ H-NMR (400 MHz, CDCl₃) δ: 1.26 (d, J=7.2 Hz, 3H), 1.28 (d, J=7.2 Hz,3H), 1.52 (s, 3H), 2.28 (s, 3H), 3.53 (s, 3H), 3.59 (s, 3H), 3.60˜3.68(m, 1H), 4.77 (s, 2H), 4.87 (s, 2H), 7.08 (d, J=8.0 Hz, 1H), 7.10˜7.32(m, 7H), 7.62 (d, J=8.0 Hz, 1H). ##STR112##

1.1 g of the isopropyl derivative prepared in the step (i) was dissolvedin methanol/water (20 ml/2 ml), followed by the addition of 1 g ofsodium hydroxide. The obtained mixture was heated under reflux for 4hours and cooled to room temperature, followed by the addition of 30 mlof 1N aqueous hydrochloric acid. The obtained mixture was extracted withethyl acetate. The organic layer was dried over anhydrous magnesiumsulfate and distilled in a vacuum to remove the solvent. The obtainedresidue was dissolved in 20 ml of acetone, followed by the addition of10 ml of concentrated hydrochloric acid. The obtained mixture wasstirred at room temperature for 30 minutes to precipitate a crystal.This crystal was recovered by filtration and washed with watersufficiently to give 0.7 g of the title compound as a pale-yellowcrystal.

m.p.: 264° to 266° C.

¹ H-NMR (400 MHz, CDCl₃) δ: 1.25 (d, J=7.0 Hz, 3H), 1.27 (d, J=7.0 Hz,3H), 1.57 (s, 3H), 2.34 (s, 3H), 3.14˜3.27 (m, 1H), 4.73 (d, J=20 Hz,1H), 4.77 (d, J=20 Hz, 1H), 7.15 (s, 1H), 7.16˜7.35 (m, 8H), 7.66 (d,J=8.0 Hz, 1H).

MS m/z (Pos, FAB): 374 (M⁺).

EXAMPLE 54 ##STR113##

The title compound was prepared from the 2-acetyl derivative prepared inthe step (g) of the Example 53 in a similar manner to that of the step(b) of the Example 40.

m.p.: 241.0° C. (dec.).

¹ H-NMR (400 MHz, CDCl₃) δ: 1.60 (s, 3H), 2.35 (s, 3H), 2.62 (s, 3H),4.82 (s, 2H), 7.11˜7.28 (m, 6H), 7.40 (s, 1H), 7.46 (br t, J=8.3 Hz,1H), 7.56 (br d, J=8.3 Hz, 1H), 14.76 (s, 1H).

EXAMPLE 55 ##STR114##

8.37 g of triphenylphosphine and 3.23 g of the ketoester prepared in theReferential Example 12 were dissolved in 20 ml of acetonitrile, followedby the addition of 3.2 ml of carbon tetrachloride in a stream ofnitrogen. The obtained mixture was stirred at room temperature in astream of nitrogen for 4 hours and poured into ether/water (120 ml/40ml). The organic layer wad washed with water, dried over anhydrousmagnesium sulfate and distilled in a vacuum to remove the solvent. Theresidue was purified by silica gel column chromatography (developer: 10%ethyl acetate/hexane) to give 3.3 g of the title compound as a yellowoil.

¹ H-NMR (400 MHz, CDCl₃) δ: 1.13 (t, J=7 Hz, 3H), 3.47 (s, 3H), 3.93 (s,3H), 4.22 (q, J=7 Hz, 2H), 4.70 (br d, J=13 Hz, 1H), 4.80 (br d, J=13Hz, 1H), 5.11 (s, 2H), 7.10˜7.30 (m, 8H), 7.70 (d, J=7 Hz, 1H).##STR115##

2.55 g of the dichloro derivative prepared in the step (a) and 0.74 mlof 8N potassium hydroxide were added to a dimethyl sulfoxide (55 ml)-water (10 ml) mixture. The obtained mixture was stirred at roomtemperature for one hour, followed by the addition of water. Theobtained mixture was acidified with 6N hydrochloric acid and extractedwith ether. The organic layer was washed with a saturated aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate andconcentrated in a vacuum. The obtained residue was purified by silicagel column chromatography (developer: 5% methanol/dichloromethane) togive 2.36 g of the title compound as a yellow oil.

¹ H-NMR (400 MHz, CDCl₃) δ: 3.46 (s, 3H), 3.86 (s, 3H), 4.74 (br d, J=14Hz, 1H), 4.84 (br d, J=14 Hz, 1H), 5.09 (s, 2H), 7.1˜7.25 (m, 8H), 7.71(d, J=8 Hz, 1H). ##STR116##

2.55 g of the carboxylic acid prepared in the step (b) was dissolved in150 ml of 1,4-dioxane, followed by the addition 1.25 ml of water and1.25 ml of concentrated sulfuric acid in this order. The obtainedmixture was stirred at room temperature for 2 hours, followed by theaddition of water. The obtained mixture was extracted with ether. Theethereal layer was washed with water, dried over anhydrous magnesiumsulfate and distilled in a vacuum to remove the solvent. The residue waspurified by silica gel column chromatography (developer: 5%methanol/dichloromethane) to give 2.0 g of the title compound as ayellow crystal.

m.p.: 152° to 154° C.

¹ H-NMR (400 MHz, CDCl₃) δ: 3.71 (s, 3H), 4.70 (br d, J=14 Hz, 1H), 4.80(br d, J=14 Hz, 1H), 6.30 (br s, 1H), 7.11 (s, 1H), 7.1˜7.25 (m, 7H),7.59 (d, J=8 Hz, 1H).

MS m/z (Pos, FAB): 402 (M⁺).

EXAMPLE 56 ##STR117##

Ethanol-water (50 ml-10 ml), 1.41 g of O-methylhydroxylamine and 2.10 gof potassium hydroxide were added to 2.38 g of the ketoester prepared inthe Referential Example 12. The obtained mixture was heated under refluxfor 45 minutes. After the completion of the reaction, the reactionmixture was poured into water. The obtained mixture was extracted withethyl acetate. The organic layer was dried over anhydrous sodium sulfateand distilled in a vacuum to remove the solvent. 1.45 g of the titlecompound was obtained. ##STR118##

1.45 g of the methoxyimino derivative prepared in the step (a) wasdissolved in methanol/water (15 ml/3 ml), followed by the addition of0.8 ml of 8N sodium hydroxide. The obtained mixture was stirred at roomtemperature. After the completion of the reaction, ice was added to thereaction mixture and the pH of the resulting mixture was adjusted to 4to 5 by the addition of 1N hydrochloric acid. The resulting mixture wasextracted with ethyl acetate under salting out. The organic layer wasdried over anhydrous sodium sulfate and distilled in a vacuum to removethe solvent. The residue was purified by silica gel columnchromatography (developer: 0 to 4% methanol/dichloromethane) to give0.69 g of the syn isomer and 0.51 g of the anti-isomer each as a reddishbrown oil. anti-isomer

¹ H-NMR (400 MHz, CDCl₃ -CD₃ OD) δ: 3.45 (s, 3H), 3.88 (s, 3H), 3.98 (s,3H), 4.76 (s, 2H), 5.04 (s, 2H), 7.0˜7.3 (m, 7H), 7.5 (s, 1H), 8.25 (d,J=7 Hz, 1H).

syn-isomer

¹ H-NMR (400 MHz, CDCl₃) δ: 3.48 (s, 3H), 3.90 (s, 3H), 4.05 (s, 3H),4.8 (s, 2H), 5.1 (s, 2H), 7.0˜7.3 (m, 10H). ##STR119##

0.69 g of the syn-carboxylic acid prepared in the step (b) was dissolvedin 5 ml of acetone, followed by the addition of 1 ml of 6N hydrochloricacid. The obtained mixture was stirred at room temperature to complete areaction. The reaction mixture was poured into water and the obtainedmixture was extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate and distilled in a vacuum to remove thesolvent. The residue was recrystallized from hexane/diethyl ether togive 0.40 g of the title compound as a pale-yellow crystal.

m.p.: 133° to 134° C.

¹ H-NMR (400 MHz, DMSO-d₆) δ: 3.82 (s, 3H), 3.84 (s, 3H), 4.7 (s, 2H),7.0˜7.25 (m, 10H), 9.23 (s, 1H).

MS m/z (Pos, FAB): 365 (M⁺). ##STR120##

0.50 g of the anti-carboxylic acid prepared in the step (b) wassuspended in 10 ml of dichloroethane, followed by the addition of 1.0 mlof trifluoroacetic acid. The obtained mixture was stirred at roomtemperature to complete a reaction. The reaction mixture was distilledin a vacuum to remove the solvent. The residue was recrystallized fromhexane/diethyl ether to give 0.35 g of the title compound as apale-yellow crystal.

m.p.: 150° C. (dec.).

¹ H-NMR (400 MHz, DMSO-d₆) δ: 3.78 (s, 3H), 3.82 (s, 3H), 4.7 (s, 2H),7.0˜7.23 (m, 8H), 7.3 (d, J=7 Hz, 1H), 9.1 (br s, 1H).

MS m/z (Pos, FAB): 365 (M⁺).

EXAMPLE 57 ##STR121##

30 ml of dichloromethane and 1.6 ml of N,N-diisopropylethylamine wereadded to 2.21 g of the α,β-unsaturated carboxylic acid prepared in theExample 2, followed by the addition of 0.69 ml of chloromethyl etherunder cooling with ice. The obtained mixture was stirred for 25 minutesunder cooling with ice, washed with 1% aqueous hydrochloric acid onceand with water once, dried over anhydrous sodium sulfate and filtered.The filtrate was distilled to remove the solvent. The obtained residuewas subjected to silica gel column chromatography to give 2.26 g of thetitle compound.

¹ H-NMR (400 MHz, CDCl₃) δ: 1.19 (t, J=7.5 Hz, 3H), 2.74 (quint, J=7.5Hz, 2H), 3.14 (s, 3H), 3.96 (s, 3H), 4.77 (br s, 2H), 5.19 (s, 2H), 6.26(t, J=7.5 Hz, 1H), 6.27 (s, 1H), 7.12 (s, 1H), 7.1˜7.3 (m, 7H), 7.64 (brd, J=8.4 Hz, 1H). ##STR122##

30 ml of dichloromethane and 1.08 g of N,N-diisopropylethylamine wereadded to 2.26 g of the methoxymethyl ester prepared in the step (a),followed by the addition of 0.59 ml of acetyl chloride under coolingwith ice. The obtained mixture was stirred under cooling with ice for 20minutes, washed with 1% aqueous hydrochloric acid and water, dried overanhydrous magnesium sulfate and filtered. The filtrate was distilled toremove the solvent. 2.56 g of the title compound was obtained as an oil.

¹ H-NMR (400 MHz, CDCl₃) δ: 1.21 (t, J=7.5 Hz, 3H), 2.03 (s, 3H), 2.79(quint, J=7.5 Hz, 2H), 3.17 (s, 3H), 3.91 (s, 3H), 4.59 (br s, 2H), 5.21(s, 2H), 6.34 (t, J=7.5 Hz, 1H), 7.0˜7.3 (m, 8H), 7.72 (d, J=8.4 Hz,1H). ##STR123##

2.56 g of the acetyloxy derivative prepared in the step (b) wasdissolved in 35 ml of acetone, followed by the addition of 1 ml of waterand 6 ml of concentrated hydrochloric acid in this order. The obtainedmixture was stirred at room temperature for 1.5 hours, followed by theaddition of water. The obtained mixture was extracted with ethylacetate. The organic layer was washed with water and a saturated aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate andfiltered. The filtrate was distilled to remove the solvent. Diisopropylether was added to the residue to precipitate a crystal. This crystalwas recovered by filtration and washed with diisopropyl ether to give2.01 g of the title compound.

m.p.: 182° to 184° C.

¹ H-NMR (400 MHz, CDCl₃) δ: 1.17 (t, J=7.5 Hz, 3H), 2.01 (s, 3H), 2.78(quint, J=7.5 Hz, 2H), 3.89 (s, 3H), 4.58 (br s, 2H), 6.39 (t, J=7.5 Hz,1H), 7.05˜7.3 (m, 8H), 7.70 (d, J=8.4 Hz, 1H).

MS m/z (Pos, FAB): 404 (M⁺), 362.

EXAMPLES 58 TO 61

The acetyl derivatives listed in Table 4 were each prepared from thephenolcarboxylic acid prepared in the Example 1, 3, 4 or 40 in a similarmanner to that of the Example 57.

                                      TABLE 4                                     __________________________________________________________________________    Ex.                                                                              Objective compound                                                         No.                                                                              structural formula and name                                                                      form .sup.1 H-NMR (400 MHz) δ, MS                                                                m.p. (°C.)              __________________________________________________________________________    58                                                                                ##STR124##        colorless crystal                                                                  2.02(s, 3H), 2.31(d, J=7.0Hz, 3H), 3.88 (s,                                   3H), 4.58(s, 2H), 6.51(q, J=7.0Hz, 1H),                                       7.06(d, J=8.0Hz, 2H), 7.14(d, J=8.0Hz, 1H),                                   7.21(s, 1H), 7.16˜7.30(m, 4H), 7.69(d,                                  J=8.0Hz, 1H) (CDCl.sub.3) (Pos, FAB): 390                                     (M.sup.+)           190˜192                  59                                                                                ##STR125##        pale- yellow crystal                                                               1.64(d, J=7.2Hz, 3H), 2.03(s, 3H), 3.87 (s,                                   3H), 4.58(s, 2H), 7.04˜7.32(m, 8H),                                     7.50˜7.60(m, 2H) (CDCl.sub.3)                                                               178˜180                  60                                                                                ##STR126##        colorless crystal                                                                  1.02(t, J=7.3Hz, 3H), 1.59(sixtet, J=7.3Hz,                                   2H), 2.00(s, 3H), 2.75(dt, J=7.5Hz, 7.3Hz,                                    2H), 3.89(s, 3H), 4.58(s, 2H), 6.40(t,                                        J=7.5Hz, 1H), 7.00˜7.30(m, 8H), 7.70(dd,                                J=8.4Hz, 1.1Hz, 1H) (CDCl.sub.3) (Pos, FAB):                                  418 (M.sup.+)       198˜200                  61                                                                                ##STR127##        pale- yellow crystal                                                               1.14(d, J=6.6Hz, 6H), 2.00(s, 3H), 3.50˜                                .60(m, 1H), 3.90(s, 3H), 4.56(brs, 1H),                                       6.18(d, J=10.0Hz, 1H), 7.04˜7.30(m, 8H),                                7.70(brd, J=8.4Hz, 1H) (CDCl.sub.3)                                                               208˜210                  __________________________________________________________________________

EXAMPLE 62 ##STR128##

1 g of the carboxylic acid prepared in the Example 1 was dissolved in 20ml of tetrahydrofuran to give a solution. 0.44 ml of triethylamine and0.45 g of diethyl chlorophosphate were added to the solution undercooling with ice. The obtained mixture was stirred for 20 minutes,followed by the addition of 0.33 ml of diethylamine under cooling withice. The obtained mixture was stirred for 30 minutes, followed by theaddition of 50 ml of ethyl acetate. The obtained mixture was washed withwater twice. The organic layer was dried over anhydrous magnesiumsulfate and distilled in a vacuum to remove the solvent. The residue waspurified by silica gel column chromatography (developer: 20 to 40% ethylacetate/hexane) to give a yellow oil. 2 ml of diisopropyl ether wasadded to the oil to precipitate a crystal. This crystal was recovered byfiltration to give 0.16 g of the title compound as a pale-yellowcrystal.

m.p.: 86° to 87° C.

¹ H-NMR (400 MHz, CDCl₃) δ: 1.01 (t, J=6.8 Hz, 3H), 1.02 (t, J=6.8 Hz,3H), 2.36 (d, J=7.2 Hz, 3H), 3.75˜3.87 (m, 4H), 3.76 (s, 3H), 4.76 (s,2H), 6.30 (s, 1H), 6.62 (q, J=6.8 Hz, 0.5H), 6.63 (q, J=6.8 Hz, 0.5H),7.10 (s, 1H), 7.10˜7.30 (m, 7H), 7.58 (dd, J=8.4 Hz, 0.8 Hz, 1H).

MS m/z (Pos, FAB): 403 (M⁺).

We claim:
 1. A compound of the formula: ##STR129## wherein R^(a) is abenzyl group; R^(b) is a hydrogen atom or a lower alkyl group;R^(c) is alower alkyl group; and R^(d) is a hydrogen atom or a group of theformula: ##STR130## wherein R^(e) is a hydroxyl group or a lower alkylgroup.
 2. A compound of the formula: ##STR131## wherein R^(a) is abenzyl group; R^(b) is a hydrogen atom or a lower alkyl group;R^(c) is ahydrogen atom or a lower alkyl group; and R^(d) is a group of theformula: ##STR132## wherein R^(e) is a hydroxyl group or a lower alkylgroup.
 3. A compound of the formula: ##STR133##
 4. A compound of theformula: ##STR134##
 5. A compound of the formula: ##STR135##